Benzoxa condensed ring compounds, process for producing the same and pharmaceutical composition comprising the same

ABSTRACT

Pharmaceutical compositions containing a benzoxazole compound and a 2,3-dihydrobenzofuran compound represented by the following formula (I) and its pharmaceutically acceptable salt: ##STR1## In the formula, any one of P, Q, R and S is a group represented by the formula: ##STR2## and R 1 , R 2  and the reining three substituents out of the substituents P to S each independently stand for various substituents. These compositions are used as an ATCAT inhibitor or for treating hyperlipidemia and atherosclerosis.

This is a continuation of application Ser. No. 08/078,274 filed asPCT/JP91/01793, Dec. 27, 1991, abandoned.

TECHNICAL FIELD

The present invention relates to a pharmaceutical composition containinga benzoxa condensed ring compound, and more specifically, it relates toa pharmaceutical composition containing a benzoxazole or2,3-dihydrobenzofuran compound, which is useful for inhibiting theaction of Acyl-Coenzyme A: Cholesterol Acyltransferase (i.e., "ACAT"herein below). Furthermore, the present invention relates to a processfor producing the above-mentioned compound and a novel compoundbelonging to the category of the above-mentioned compound.

BACKGROUND ART

As is well known in the art, atherosclerosis is a very important factorcausative of various cardiovascular diseases, and extensive andintensive studies have been conducted with a view to suppression of theprogress of atherosclerosis or regression of atherosclerosis. Inparticular, the efficacy of a drug for lowering cholesterol in the serumor arterial wall is recognized. However, an ideal drug having asignificant clinical effect and less liable to occurrence of an adverseeffect has not been realized in the art.

In recent years, it has become apparent that the accumulation of acholesterol ester in an arterial wall is an important factor causativeof the progress of atherosclerosis. Therefore, a lowering in thecholesterol level in the blood is useful for suppression of the progressof atherosclerosis and regression of the atherosclerosis.

Cholesterol in foods is esterified in tunica mucosa intestini tenuis andthen incorporated as chylomicron in the blood. It is known that ACATplays an important role in the formation of a cholesterol ester in thetunica mucosa intestini tenuis or arterial wall. Therefore, it isconsidered that the inhibition of ACAT in the tunica mucosa intestinitenuis and the prevention of the esterification can prevent theabsorption of the cholesterol, and the cholesterol level of the bloodcan be lowered.

In the arterial wall, the cholesterol is accumulated as a cholesterolester. Therefore, it is expected that the inhibition of ACAT in thearterial wall can effectively prevent the accumulation of thecholesterol ester.

Thus, an ACAT inhibitor is considered likely to become a drug useful fortreating hyperlipidemia and atherosclerosis through the prevention ofthe cholesterol in intestinum tenue and the accumulation of thecholesterol in the arterial wall.

For example, urea derivatives (see, for example, J. Med. Chem., vol. 29,1131 (1986) and Japanese Unexamined Patent Publication (Kokai) Nos.63-316761 (which corresponds to EP-A-293880 and 1-93569 (whichcorresponds to EP-A-297610)) and amide derivatives (see, for example,Japanese Examined Patent Publication (Kokoku) No. 63-54718 (whichcorresponds to U.S. Pat. No. 4,296,240 and U.S. Pat. No. 4,297,349) andJapanese Unexamined Patent Publication (Kokai) No. 63-253060 (whichcorresponds to U.S. Pat. No. 4,716,175) have hitherto been reported asthe above-mentioned ACAT enzyme inhibitor. In all the above-mentionedcompounds, although the aromatic nucleus is bonded to a nitrogen atom ofa urea or amide portion directly or through an alkylene group, nocompound is disclosed wherein a benzoxazole condensed ring, that is,benzoxazole or 2,3-dihydrobenzofuran ring, is directly bonded to anitrogen atom of the urea or amide portion.

It is known that some compounds wherein benzoxazole or2,3-dihydrobenzofuran ring is directly bonded to a nitrogen atom of aurea or amide portion can be used as an intermediate for synthesizingdrugs, insecticides, vermifuges, bacteriocides for agriculture andgardening, herbicides, photographic materials, etc. However, it isunknown whether or not they have an ACAT inhibitory activity. Examplesof the former compound known in the art include compounds for use as aninsecticide, wherein a substituted arylcarbonyl group is bonded to oneof the nitrogen atoms of a ureylene group bonded to the benzene ring(see Japanese Unexamined Patent Publication (Kokai) No. 64-42474);compounds for use as a vermifuge, wherein a substituted or unsubstitutedphenylamide group ##STR3## is bonded to the benzene ring (see CanadianPatent No. 842258); calcimycin (A-23187) known as Ca ionophore andderivatives thereof (see J. Am. Chem. Soc., 104, 1436 (1982); andJapanese Unexamined Patent Publication (Kokai) No. 62-26283 (whichcorresponds to Derwent Abstract 87-74940)) and several derivatives foruse as an optomagnetic material and a heat-resistant material (seeJournal of The Society of Organic Synthetic Chemistry, vol. 29, p. 717;and Japanese Examined Patent Publication (Kokoku) No. 64-53303 (whichcorresponds to U.S. Pat. No. 4,400,294)). Examples of the lattercompound known in the art include compounds for use as a herbicide,wherein a chloroacetamide group is bonded to the benzene ring (seeJapanese Patent Unexamined Patent Publication (Kokai) No. 60-109585(which corresponds to Derwent Abstract 85-181198)); compounds for use asa bacteriocide for agriculture and gardening, wherein a substitutedphenylamide group is bonded to the benzene ring (see Japanese UnexaminedPatent Publication (Kokai) No. 60-215680 (which corresponds to DerwentAbstract 85 -307995)); compounds for use as a starting compound for apigment, wherein an acetylacetamide group is bonded to the benzene ring(see Japanese Examined Patent Publication (Kokoku) No. 47-7715 (whichcorresponds to U.S. Pat. No. 3,634,462)); compounds for use as aherbicide, wherein a substituted aryloxyisopropylamide group is bondedto the benzene ring (see Japanese Unexamined PCT Patent Publication(Kohyo) No. 61-501991 (which corresponds to WO-A-86-2642 andEP-A-199794)); compounds for use as an antiallergic drug, wherein atetrazole group is located as an indispensable group at the 2-positionand a substituted phenylamide group is bonded to the benzene ring (seeJapanese Unexamined Patent Publication (Kokai) No. 2-138242 (whichcorresponds to U.S. Pat. No. 4,780,469, U.S. Pat. No. 4,847,257 and U.S.Pat. No. 4,939,141)); compounds for use as an analgesic, wherein anacetamide group is bonded to the benzene ring (see Spanish Patent No.512355); compounds for use as a herbicide, wherein a methyl orcyclopropyl group is bonded to one nitrogen atom of a ureylene groupbonded to the benzene ring (see Canadian Patent No. 117860); andcompounds for use as a photosensitive material for silver halide colorphotography, wherein a substituted alkylamide group or a substitutedphenylamide group is bonded to the benzene ring (see Japanese UnexaminedPatent Publication (Kokai) Nos. 61-250642 (which corresponds to DerwentAbstract 86-335324) and 61- 233742 (which corresponds to DerwentAbstract 86-315479)). The above-described prior art documents are,however, silent on the fact that benzoxazole or 2,3-dihydrobenzofuranderivatives, including the above-described known compounds, have an ACATinhibitory activity.

DISCLOSURE OF THE INVENTION

Accordingly, an object of the present invention is to provide apharmaceutical composition having an ACAT enzyme inhibitory activity andcapable of exhibiting an excellent therapeutic effect through a loweringin the level of cholesterol in the blood or arterial wall, a novelderivative containing a benzoxa condensed ring capable of exhibiting asignificant effect and a process for producing the same.

The present inventors have made extensive and intensive studies with aview to providing compounds significantly superior to knownanti-hyperlipidemic agents and anti-atheroscleotic agents and, as aresult, have unexpectedly found that certain amides or urea derivativeshaving a benzoxazole or 2,3-dihydrobenzofuran ring have not only astrong ACAT inhibitory activity but also strong anti-hyperlipidemicactivity and anti-atheroscleotic activity, which has led to thecompletion of the present invention.

In accordance with the present invention, the above-mentioned object ofthe present invention can be attained by providing a pharmaceuticalcomposition comprising a benzoxa condensed ring compound represented bythe following formula (I) or its pharmaceutically acceptable salt in anamount effective for inhibiting the action of Acyl-coenzyme A:Cholesterol Acyltransferase: ##STR4## wherein any one of P, Q, R and Sis a group represented by the formula: ##STR5## with the remaining threesubstituents being independently a group represented by the formula--R₃,

wherein R₁ stands for a group selected from the group consisting of:

(i) an unsubstituted cycloalkyl or cycloalkenyl group or a cycloalkyl orcycloalkenyl group substituted at a position other than the 1-positionwith the substituent being a C₁ -C₁₄ alkyl, alkoxy, acylamino,monoalkylamino, alkyloxycarbonyl, acyl or acyloxy group or a C₂ -C₂₆dialkylamino group;

(ii) a group represented by the formula: ##STR6## wherein R₉ and R₁₀each independently stands for a hydrogen atom or a lower alkyl group, ormay combine with each other to form a C₃ -C₇ carbon ring; and R₁₁ standsfor a substituted or unsubstituted C₁ -C₁₉ alkyl, C₂ -C₁₉ alkenyl, C₆-C₁₀ aryl, C₇ -C₁₉ arylalkyl or C₁ -C₁₉ acyl group or acyl group havinga C₄ -C₁₉ aromatic ring, provided that the substituent when said groupsare substituted is a halogen atom, an amino, nitro, cyano, carboxyl orhydroxyl group, a C₁ -C₁₆ alkyl, alkoxy, acylamino, monoalkylamino,alkyloxycarbonyl, acyl or acyloxy group, or a C₂ -C₂₆ dialkylaminogroup; or R₁₁ stands for a group represented by the formula:

    --A--X--B

wherein A stands for a C₁ -C₁₂ alkylene chain;

X stands for an oxygen atom, a sulfur atom, or a group represented bythe formula: ##STR7## wherein R₁₂ stands for a hydrogen atom or a loweralkyl or acyl group or may combine with B to form a cyclic amine,provided that, when a cyclic amine is formed, an oxygen atom, a sulfuratom, a nitrogen atom or a nitrogen atom substituted with a lower alkylor arylalkyl group may be contained as a constituent member of the ring;and

B stands for a substituted or unsubstituted alkyl, aryl or arylalkylgroup, provided that the substituent when said groups are substituted isa halogen atom, an amino, nitro, cyano, carboxyl or hydroxyl group, a C₁-C₁₂ alkyl, alkoxy, monoalkylamino, acylamino, alkyloxycarbonyl, acyl oracyloxy group, or a C₂ -C₂₀ dialkylamino group; and

(iii) a substituted or unsubstituted aryl group or a group representedby the formula: ##STR8## wherein any one of P_(b), Q_(b), R_(b) andS_(b) represents a bond with the remaining three substituentsindependently standing for a group represented by the formula --R₃,provided that, when the aryl group is substituted, the substituent ispresent at the o-, m- or p-position and a halogen atom, an amino, nitro,cyano, carboxyl or hydroxyl group, a C₁ -C₁₆ alkyl, alkoxy,monoalkylamino, acylamino, alkyloxycarbonyl, acyl or acyloxy group, or aC₂ -C₂₆ dialkylamino group; and the alkyl portion of said groups may beinterrupted by: ##STR9## wherein R₁₃ stands for a hydrogen atom or alower alkyl, acyl or arylalkyl group,

arylene or arylenoxy, or 1 to 3 hydrogen atoms on the carbon atom may besubstituted with an aryl or aryloxy group, a halogen atom or a cyanogroup, or the aryl portion as the substituent may be substituted with ahalogen atom, an amino, nitro, cyano, carboxyl or hydroxyl group, or alower alkyl, alkoxy, monoalkylamino, dialkylamino, acylamino,alkyloxycarbonyl, acyl or acyloxy group;

R₂ stands for a hydrogen atom or a C₁ -C₈ alkyl group;

each R₃ independently stands for a hydrogen atom, a halogen atom, anamino, nitro, cyano, carboxyl or hydroxyl group, C₁ -C₂₀ alkyl, alkoxy,acylamino, monoalkylamino, alkyloxycarbonyl, acyl or acyloxy group, or aC₂ -C₂₆ dialkylamino group; and the alkyl portion of said groups may beinterrupted by: ##STR10## wherein R₁₃ stands for a hydrogen atom or alower alkyl, acyl or arylalkyl group,

arylene or arylenoxy, or 1 to 3 hydrogen atoms on the carbon atom may besubstituted with an aryl or aryloxy group, a halogen atom or a cyanogroup, or the aryl portion as the substituent may be substituted with ahalogen atom, an amino, nitro, cyano, carboxyl or hydroxyl group, a C₁-C₂₀ alkyl, alkoxy, monoalkylamino, acylamino, alkyloxycarbonyl, acyl oracyloxy group, or a C₂ -C₂₆ dialkylamino group; and

Z stands for a linking group which combines with an O atom, a carbonatom of the benzene ring, to which the O atom is bonded, and a carbonatom adjacent to said carbon atom to form a five-membered ring and isrepresented by the formula: ##STR11## wherein R₄ stands for a hydrogenatom, a C₁ -C₂₀ alkyl, alkenyl or alkynyl group, or a substituted orunsubstituted aryl group, provided that the substituent when the arylgroup is substituted is a halogen atom, an amino, nitro, cyano, carboxylor hydroxyl group, a C₁ -C₂₀ alkyl, alkoxy, monoalkylamino, acylamino,alkyloxycarbonyl, acyl or acyloxy group, or a C₂ -C₂₆ dialkylaminogroup; and

R₅, R₆, R₇ and R₈ each independently stand for a hydrogen atom or a C₁-C₂₀ alkyl group, or R₅ and R₆ or R₇ and R₈ combine with a carbon atombonded thereto to form a C₅ -C₇ carbon ring; and n is 0 or 1.

Further, the present invention provides a novel benzoxa condensed ringcompound represented by the following formula (I_(a)) or itspharmaceutically acceptable salt which constitutes a preferredembodiment of the above-described pharmaceutical composition: ##STR12##wherein P_(a), Q_(a) and R_(a) each independently stand for a hydrogenatom, a halogen atom, or an amino, nitro, cyano, carboxyl or hydroxylgroup, a C₁ -C₂₀ alkyl, alkoxy, acylamino, monoalkylamino,alkyloxycarbonyl, acyl or acyloxy group, or a C₂ -C₂₆ dialkylaminogroup; and the alkyl portion of said groups may be interrupted by:##STR13## wherein R₁₃ stands for a hydrogen atom or a lower alkyl, acylor arylalkyl group,

arylene or arylenoxy, or 1 to 3 hydrogen atoms on the carbon atom may besubstituted with an aryl or aryloxy group, a halogen atom or a cyanogroup, and the aryl portion as the substituent may be substituted with ahalogen atom, an amino, nitro, cyano, carboxyl or hydroxyl group, a C₁-C₂₀ alkyl, alkoxy, monoalkylamino, acylamino, alkyloxycarbonyl, acyl oracyloxy group, or a C₂ -C₂₆ dialkylamino group, provided that R_(a)stands for a group other than the hydrogen atom among the groupsdescribed above in connection with the definition of Ra; and

R₁, R₂, Z and n are as defined above.

Further, the present invention provides the following processes forproducing compounds represented by the formula (I), that is,

(A) a process for producing a compound represented by the formula (I)wherein n is 1, and its pharmaceutically acceptable salt, comprisingreacting an isocyanate represented by the following formula (II):##STR14## wherein m is an integer of 0 to 3; and

R₃ and Z are as defined above, with an isocyanate represented by thefollowing formula (III): ##STR15##

wherein R₁ and R₂ are as defined above, and optionally converting thereaction product to a salt;

(B) a process for producing a compound represented by the formula (I)wherein n is 1, and its pharmaceutically acceptable salt, comprisingreacting an amine represented by the following formula (IV): ##STR16##

wherein m, R₃ and Z are as defined above, with an isocyanate representedby the following formula (V):

    O═C═N--R.sub.1                                     (V)

wherein R₁ is as defined above, and optionally converting the reactionproduct to a salt; and

(C) a process for producing a compound represented by theabove-mentioned formula (I) wherein n is 0, and its pharmaceuticallyacceptable salt, comprising reacting an amine represented by the formula(IV) with a carboxylic acid represented by the following formula (VI) orits reactive derivative:

    R.sub.1 COOH                                               (VI)

wherein R₁ is as defined above, and optionally converting the reactionproduct to a salt.

Other objects and advantage of the present invention will be apparentfrom the following description.

BEST MODE FOR CARRYING OUT THE INVENTION

In accordance with to the present invention, there is provided apharmaceutical composition comprising a compound, which partiallyincludes a known compound, for use in the treatment of diseasesdeveloped by the action of ACAT, which compounds are unknown to have anACAT inhibitory activity and to be useful for treating the diseases. Inthe present invention, the term "treatment" is used in such a conceptthat the compound represented by the formula (I) is used for any oftherapeutic and preventive purposes.

Furthermore, in accordance with the present invention, there is provideda novel compound which can be used particularly advantageously for thetreatment of the above-mentioned diseases.

In the description in connection with the compounds and derivatives inthe present specification, the term "lower" is used in such meaningthat, in groups to which the term is affixed, for example, alkyl,alkenyl, alkynyl, alkoxy, acylamino, mono- or di-alkylamino, acyl andacyloxy groups and the alkyl, alkenyl or alkynyl portion of arylalkylgroups may take any of chain (straight-chain or branched) and cyclicforms having a 1 to 6 carbon atoms, unless otherwise specified.Accordingly, specific examples of the lower alkyl group include methyl,ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl,pentyl, neopentyl, hexyl, cyclopropyl, cyclohexyl and cyclopropylmethyl.

Also when the above-described groups have a larger number of carbonatoms, they are used in such meaning that they may take any of chain(straight-chain or branched) and cyclic forms, unless otherwisespecified.

The expression "the alkyl portion is interrupted by: ##STR17## or thelike" is intended to mean that a suitable carbon-carbon bond of thealkyl chain may take a bonding form, such as carbon-O-carbon.

In the compounds of the formula (I) used for attaining the object of thepresent invention, Z in the formula combines with an oxygen atom bondedto the benzene ring, a carbon atom of the benzene ring, to which theoxygen atom is bonded, and a carbon atom adjacent to said carbon atom toform a five-membered ring, and the compounds of the formula (I) areroughly classified into groups of compounds, that is, benzoxazolederivatives (i.e., Z being a linking group represented by the formula:##STR18## and 2,3-dihydrobenzofuran derivatives (i.e., Z being a linkinggroup represented by the formula: ##STR19## and further classified intoamide derivatives wherein each n is 0, and urea derivatives wherein n is1.

More specifically, the benzoxa condensed ring compounds belonging to thefirst group of compounds according to the present invention arebenzoxazole derivatives represented by the following formula (I-1):##STR20## wherein P, Q, R, S and R₄ are as defined above, and the secondgroup of compounds are 2,3-dihydrobenzofuran derivatives represented bythe following formula (I-2): ##STR21## wherein P, Q, R, S, R₅, R₆, R₇and R₈ are as defined above.

In the formulae (I-1) and (I-2), the groups Q to S are of equalsignificance from the viewpoint of the object of the present invention,and any one of these groups stands for a group represented by theformula: ##STR22## with the remaining substituents each independentlystanding for a group R₃. Therefore, the group represented by theabove-described formula may be bonded to any of the 4- to 7-positions(P, Q, R, S) in the benzene ring of the compounds represented by theformulae (I-1) and (I-2). However, compounds wherein the grouprepresented by the above-mentioned formula is bonded to the 7-position(S) is particularly preferred from the viewpoint of the intended drugefficacy and are important also because most of them are novelcompounds.

In the formulae (I-1) and (I-2), the R₁ stands for (i) an unsubstitutedcycloalkyl or cycloalkenyl group, or a cycloalkyl or cycloalkenyl groupsubstituted at its position other than the 1-position; a grouprepresented by the formula: ##STR23## a substituted or unsubstitutedaryl group or a group represented by the formula: ##STR24## wherein thebonding group substitutes for the group: ##STR25## with the remaininggroups being as defined above.

In the R₁, favorable specific examples of the unsubstituted cycloalkylor cycloalkenyl group or cycloalkyl or cycloalkenyl group substituted atits position other than the 1-position include cyclopentyl, cyclohexyl,cycloheptyl, 1-cyclohexen-1-yl, 4 -hexylcyclohexyl and4-decyloxycyclohexyl.

When the R₁ stands for a group represented by the formula: ##STR26## theR₉ and R₁₀ each independently stand for a hydrogen atom or a lower alkylgroup, or combine with each other to form a C₃ -C₇ carbon ring.

Examples of the lower alkyl group include those described above, andwhen the R₉ and R₁₀ combine with each other to form a C₃ -C₇ carbonring, examples of the R₁ include a group represented by the followingformula: ##STR27##

In the R₁₁, favorable examples of the substituted or unsubstituted C₁-C₁₉ alkyl include, besides the above-described lower alkyls, isohexyl,octyl, decyl, undecyl, dodecyl, tridecyl, pentadecyl, hexadecyl,heptadecyl, nonadecyl, icosyl, 1,1-dimethylhepthyl, 1,1-dimethylundecyl,1,1,12,12-tetramethyltridecyl, 1-methyltridecyl, 1-decylcyclohexyl,1-decylcyclopentyl, 1-dodecylcyclopropyl, 1-cyclohexyl-1-methylethyl,1-ethyloctyl and 10,10-dimethylundecyl.

In the R₁₁, examples of the C₂ -C₁₉ alkenyl include vinyl, allyl,butenyl, hexenyl, 8-tridecenyl, 8-heptadecenyl, 9-octadecenyl,8,11-heptadecanedienyl, 1,1-dimethyl-8-nonenyl, cyclohexenylmethyl,2-cyclopenten-1-yl, 2,4-cyclopentadien-1-yl, 3-cyclohexen-1-yl and2,5-cyclohexadien-1-yl.

Specific examples of the R₁₁ when the R₁₁ stands for a C₆ -C₁₀ arylgroup include phenyl, naphthyl, pyridyl and thienyl. Accordingly, inthis case, specific examples of the R₁ include benzyl,1-phenylcyclopentyl, 1-phenylethyl and 1-methyl-1-(2-pyridyl)ethyl.Favorable specific examples of the R₁ when the R₁₁ stands for a C₇ -C₁₉aryl alkyl include 2-phenylethyl, 8-phenyloctyl,1,1-dimethyl-11-phenylundecyl, 1-benzylcyclopentyl,(1-phenylcyclopentyl)methyl,1,1-dimethyl-4-(1-methyl-1,2,3,4-tetrahydroquinolin-6-yl)butyl,1,1-dimethyl-7-pyridylheptyl, 2,2-diphenylethyl,1,1-dimethyl-6-phenylhexyl, 1,1-dimethyl-7-phenylheptyl,1,1-dimethyl-5-phenylpentyl and 1,1-dimethyl-4-phenylbutyl.

Favorable examples of the R₁₁ when the R₁₁ stands for a C₁ -C₁₉ chainacyl group, C₄ -C₁₉ cyclic hydrocarbon acyl group or a acyl group havinga aromatic ring include groups wherein a carbonyl group is bonded to afavorable group of the above-described alkyl, cyclic alkyl, chainalkenyl, cyclic alkenyl, aryl and arylalkyl groups.

The R₁₁ embraces also groups wherein one or more hydrogen atoms,preferably 1 to 3 hydrogen atoms, on carbon(s) in the chain or oncarbons constituting the ring are substituted with halogen atoms (forexample, fluorine, chlorine, bromine and iodine, preferably fluorine andchlorine), amino, nitro, cyano, carboxyl and hydroxyl groups and furtherC₁ -C₁₆ alkyl (as described above), alkoxy (for example, lower alkoxy,such as methoxy, ethoxy and propoxy, pentadecanoxy, decyloxy andoctyloxy), acylamino (for example, lower acylamino, such as acetamide,propionylamino, butyrylamino and heptanoylamino, and lauroylamino andpalmitoylamino), mono-or di-alkylamino (for example, methylamino,ethylamino, dimethylamino, diethylamino and decanylamino),alkyloxycarbonyl (for example, groups wherein a carbonyl group is bondedto the above-described alkoxy, such as methoxycarbonyl andethoxycarbonyl), acyl (formyl, acetyl, propionyl, isovaleryl, pivaloyl,myristoyl, palmitoyl, etc.), and acyloxy (acetyloxy, pivaloyloxy,myristoyloxy, etc.). Specific examples of the R₁ having R₁₁ substitutedwith the above-described groups include 1,1-dimethyl-11-chloroundecyl,1,1-dimethyl-7-bromoheptyl, 9-ethoxycarbonylnonyl,1,1-dimethyl-11-hydroxyundecyl, 1,1-dimethyl-10-carboxyldecyl,1-(4-dimethylaminophenyl)cyclopentyl, 1-methyl-1-(4-chlorophenyl)ethyl,1-methyl-1-(4-octyloxyphenyl)ethyl,[1-(4-chloro)phenylcyclopentyl]methyl,[1-(4-dimethylamino)phenylcyclopentyl]methyl,1,1-dimethyl-4-(4-isobutyl)phenylbutyl,1,1-dimethyl-4-(4-hexyloxy)phenylbutyl,1,1-dimethyl-2-(4-decyloxy)phenylethyl,1,1-dimethyl-2-(4-decylamino)phenylethyl and1,1-dimethyl-7-(4-chloro)phenylheptyl groups.

Alternatively, the R₁₁ may stand for a group represented by the formula--A--X--B wherein A stands for a C₁ -C₁₂ alkylene chain; X stands for anoxygen atom, a sulfur atom, or a group represented by the formula:##STR28## wherein R₁₂ stands for a hydrogen atom or a lower alkyl oracyl group or may combine with B to form a cyclic amine, provided that,when a cyclic amine is formed, an oxygen atom, a sulfur atom, a nitrogenatom or a nitrogen atom substituted with a lower alkyl or arylalkylgroup may be contained as a constituent member of the ring; and B standsfor a substituted or unsubstituted alkyl, aryl or arylalkyl group. Thealkylene in the A is a divalent group formed by further eliminating onehydrogen atom from the alkyl group, and examples thereof include thosecorresponding to the alkyl groups specifically described above. Examplesof the lower alkyl and acyl groups in the R₁₂ include the same groups asthose described above in connection with the lower alkyl group and acylgroup. Favorable specific examples of the cyclic amine when R₁₂ combineswith B to form a cyclic amine include 1-pyrrolidinyl, piperidino,morpholino, thiomorpholino, 4-methyl-1-piperazinyl and4-benzyl-1-piperazinyl. The alkyl group and arylalkyl group in the Bhave the same meaning as the alkyl group and arylalkyl group definedabove, and preferred examples thereof are also the same as those of thealkyl group and arylalkyl group described above.

Also when the R₁₁ stands for a group represented by the formula--A--X--B, each group may be substituted in the same manner as thatdescribed above in connection with each group of R₁₁. Favolable specificexamples of the R₁ having R₁₁ substituted with the above-describedgroups include 6-isobutoxyhexyl, 6-p-chlorophenoxyhexyl,5-p-dimethylaminophenoxypentyl, 5-isohexyloxy-1,1-dimethylpentyl,7-isohexyloxy-1,1-dimethylheptyl, 7-isobutoxy-1,1-dimethylheptyl,7-neopentyloxy-1,1-dimethylheptyl, 5-p-chlorophenoxy-1,1-dimethylpentyl, 6-p-chlorophenoxy-1,1-dimethylhexyl,7-p -chlorophenoxy-1,1-dimethylheptyl, 1,1-dimethyl-7-p-tolyloxyheptyl,5-(p-tert-butylphenoxypentyl,1,1-dimethyl-6-p-dimethylaminophenoxyhexyl,1,1-dimethyl-7-p-dimethylaminophenoxyheptyl,7-isopropylamino-1,1-dimethylheptyl, 7-benzylamino-1,1-dimethylheptyl,7-(N-benzyl-N-methylamino)-1,1-dimethylheptyl,7-(N-p-chlorobenzyl-N-methylamino)-1,1-dimethylheptyl,7-(N-p-chlorophenyl-N-methylamino)-1,1-dimethylheptyl,1,1-dimethyl-7-piperidinoheptyl,1,1-dimethyl-7-(4-methyl-1-piperazinyl)heptyl,7-(4-benzyl-1-piperazinyl)-1,1-dimethylheptyl,5-(4-benzyl-1-piperazinyl)-1,1-dimethylpentyl,6-(p-chlorophenylthio)-1,1-dimethylhexyl,1,1-dimethyl-6-p-nitrophenoxyhexyl, 1,1-dimethyl-6-p-fluorophenoxyhexyl,1,1-dimethyl-6-p-aminophenoxyhexyl,1,1-dimethyl-6-(2,4-dichloro)phenoxyhexyl,1,1-dimethyl-7-p-fluorophenoxyheptyl,1,1-dimethyl-6-p-hexyloxyphenyloxyhexyl, 1,1-dimethyl-7-morpholinoheptyland 1,1-dimethyl-6-cyclohexylethylhexyl.

When the R₁ stands for a substituted or unsubstituted aryl group, thearyl group has the same meaning as the aryl group defined above inconnection with the R₁₁, except that the aryl group is bonded to thecarbon atom of the carbonyl group or the nitrogen atom of the grouprepresented by the formula ##STR29## of an amide or urea portion of theformula (I-1) or (I-2). The substituted aryl group has a suitablesubstituent at the o-, m- or p-position relative to the site of bondingto the amide or urea (ureylene) portion. Preferred specific examples ofthese substituents include the same groups as those described above inconnection with the R₁₁. When these substituents have a particularlylong chain alkyl portion, the alkyl portion may be interrupted by:##STR30## (wherein R₁₃ stands for a hydrogen atom or a lower alkyl oracyl group), arylene or arylenoxy. The term "arylene" used herein isintended to mean a divalent group formed by eliminating one hydrogenatom from an aryl group, and specific examples thereof include thoseformed by eliminating one hydrogen atom from the aryl group specificallydescribed above. The alkyl portion and aryl (or arylene) portion ofthese substituents as well may be substituted with one or moresubstituents, preferably 1 to 3 substituents, as described aboveconnection with the R₁₁. Among them, particularly preferred examplesinclude p-fluorophenyl, p-decylphenyl, p-methoxyphenyl,p-isohexyloxyphenyl, p-decyloxyphenyl, p-butyrylaminophenyl,p-(N-butyl-N-methylamino, phenyl, p-valeryloxyphenyl, m-heptanoylphenyl,4-[6-(4-chlorophenyloxy)hexyloxy]phenyl, 4-decylaminophenyl,4-decanamidephenyl, m-decyloxyphenyl,4-[6-(4-dimethylaminophenyloxy)-hexyloxy]phenyl, 3-chloro-4-decyloxyphenyl, 4-[6-(N-methyl-N-benzylamino)hexyloxy]phenyl and3-dimethylamino-4-decyloxyphenyl groups.

Further examples of the R₁ include a group represented by the formula:##STR31## wherein P_(b) to S_(b) and Z have the same meaning thecorresponding P_(a) to S_(b) and Z described above, except that one ofthe P_(b) to S_(b) stands for a linking group instead of the grouprepresented by the formula: ##STR32##

When the R₁ has the above-described group, examples of the compoundrepresented by the formula (I) include compounds comprising combinationof the following moieties. ##STR33##

Therefore, the compound represented by the formula (I) include also acompound having such a structure that the above-described individualmoieties are linked together through the divalent linking group of theureylene group or amide group indicated at the center of theabove-described structural formulae and the linking group of the leftand right condensed ring moieties.

The R₂ stands for a hydrogen atom or a C₁ -C₈ alkyl group. Favorableexamples of the alkyl group include, besides the above-describedspecific examples of the lower alkyl group, heptane, octane,cyclohexylmethyl and cyclohexylethyl.

When P, Q, R and S in the formulae (I-1) and (I-2) stand for a groupother than the group represented by the formula: ##STR34## the remainingthree groups each independently stand for a hydrogen atom, a halogenatom, an amino, nitro, cyano, carboxyl or hydroxyl group, a C₁ -C₂₀alkyl, alkoxy, acylamino, monoalkylamino, alkyloxycarbonyl, acyl oracyloxy group, or a C₂ -C₂₆ dialkylamino group; and the alkyl portion ofthese groups may be interrupted by: ##STR35## wherein R₁₃ stands for ahydrogen atom or a lower alkyl, acyl or arylalkyl group,

arylene or arylenoxy, or 1 to 3 hydrogen atoms on the carbon atom may besubstituted with an aryl or aryloxy group, a halogen atom or a cyanogroup, or the aryl portion as the substituent may be substituted with ahalogen atom, an amino, nitro, cyano, carboxyl or hydroxyl group, a C₁-C₂₀ alkyl, alkoxy, monoalkylamino, acylamino, alkyloxycarbonyl, acyl oracyloxy group, or a C₂ -C₂₆ dialkylamino group.

The meaning and specific examples of these groups are the same as themeaning and specific examples of the corresponding groups describedabove in connection with the R₁. More preferably, when any three of thegroups P, Q, R and S stand for a group other than the group representedby the formula: ##STR36## although these three groups may be the same ordifferent, if the R₁ stands for a group having a large number ofconstituent atoms (number of carbon atoms: 10 to 20), these groupspreferably comprise a group having a small number of constituent atoms,for example, a hydrogen atom, a halogen atom (particularly, fluorine,chlorine or bromine), an amino, nitro, cyano, carboxy or hydroxyl group,a lower alkyl group (particularly, methyl, ethyl, propyl or isopropyl),a lower alkyloxy group (particularly, methoxy, ethoxy or propoxy), alower acylamino group (particularly, acetamide or propionylamide), amono- or di-lower alkylamino group (particularly, methylamino,ethylamino or dimethylamino), a lower alkyloxycarbonyl group(particularly, methoxycarbonyl or ethoxycarbonyl), a lower acyl group(particularly, acetyl, propionyl or butyryl), or a lower acyloxy group(particularly, acetyloxy or propionyloxy). On the other hand, when theR₁ is a group having a small number of constituent atoms (number ofcarbon atoms: 6 or less), it is preferred that at least one group amongthe P, Q, R and S except for the group represented by the formula:##STR37## be a group having a large number of constituent atoms.Specific examples of the group having a large number of constituentatoms include decyloxy, decanoylamide, dodecyloxy,4-decyloxybenzoylamide, decyl, decylamino, 2,2-dimethyldodecaneamido,6-(4-chlorophenyl)hexyloxy, 4-(6-phenyloxy)hexyloxybenzoyl and6-(N-methyl-N-4-chlorobenzyl)aminohexyloxy.

As described above, the compound represented by the formula (I) whereina group represented by the formula: ##STR38## is bonded to the7-position (S) is particularly preferred from the viewpoint of drugefficacy. In this case, it is still preferred for the 6-position (R) tobe a group other than a hydrogen atom from the viewpoint of the drugefficacy. In particular, when the R₁ contained in the group bonded tothe 7-position stands for a group having a large number of constituentatoms, it is preferred for the substituent at the 6-position to be alower alkyl, a lower alkoxy or a halogen.

when the R₄ in the formula (I-1) stands for a C₁ -C₂₀ alkyl group,specific examples of such an alkyl group are the same as those of thealkyl group described above in connection with the definition of P, Q, Rand S. When the R₄ stands for an alkenyl group, the alkenyl group ispreferably a lower alkenyl group and examples thereof include vinyl,propenyl and cyclohexenyl. When the R₄ stands for an alkyl group, thealkynyl group is preferably a lower alkynyl group and examples thereofinclude ethynyl and propynyl. When the R₄ stands for a substituted orunsubstituted aryl group, examples of the substituent are the same asthose of the substituent at the site of the aryl in the definition ofthe R₁₁ and preferred examples thereof include a halogen atom, a loweralkyl, a lower alkoxy, a lower acyl, a lower alkylamino or a loweralkyloxycarbonyl. When the R₄ stands for the above-described aryl group,favorable specific examples of the aryl group include phenyl, pyridyl,thienyl, 4-methylphenyl, 4-chlorophenyl, 4-methoxyphenyl,4-decanoxyphenyl and 3-nitrophenyl.

When the R₅, R₆, R₇ and R₈ in the formula (I-2) stand for a C₁ -C₂₀alkyl group, specific examples of such an alkyl group are the same asthose of the alkyl group described in connection with the R₄. Amongthem, a lower alkyl, such as methyl, ethyl, propyl and isopropyl, areparticularly preferred. These four groups may be the same or different.It is preferred that the R₅ and R₆ stand for a hydrogen atom with the R₇and R₈ standing for a lower alkyl group. When R₅ and R₆ or R₇ and R₈combine with a carbon atom bonded thereto to form a C₅ -C₇ carbon ring,favorable specific examples of such a carbon ring include C₅ -C₇ carbonrings described above in connection with the R₁₁.

Compounds represented by the formula (Ia), more specifically,benzoxazole compounds represented by the following formula (Ia-1):##STR39## wherein P_(a), Q_(a), R_(a), R₁, R₂, R₄ and n are as definedabove, provided that R_(a) stands for a group other than a hydrogenatom, and 2,3-dihydrobenzofuran compounds represented by the followingformula (Ia-2): ##STR40## wherein P_(a), Q_(a), R_(a), R₁, R₂, R₅, R₆,R₇, R₈ and n are as defined above, provided that R_(a) stands for agroup other than a hydrogen atom, are novel compounds not described inany conventional technical literature. Further, when the structuralformula representing the compound of the present invention has anasymmetric carbon, the compound of the present invention includes allpossible optical isomers.

Examples of compounds comprising specific combinations of groups willnow be described for the purpose of more specifically describing thecompounds and novel compounds used in the pharmaceutical composition ofthe present invention. In the following synoptical tables, code G isused according to need to represent the formula: ##STR41##

      Compound No. R˜S R.sub.4 R.sub.1 R.sub.2 n      101 P,R = CH.sub.3 Q = Cl, S = G (CH.sub.2).sub.8      CH.sub.3     ##STR42##      H 1  102 R = OCH.sub.3 S = G P,Q =      H CH.sub.3     ##STR43##      H 1  103 P = H Q,R = CH.sub.3 S =      G     ##STR44##      ##STR45##      H 1  104 P = G, Q,R = CH.sub.3 S =      H     ##STR46##      ##STR47##      H 1        Compound No. R˜S R.sub.4 R.sub.9 R.sub.10 R.sub.11 R.sub.2     n       105 S = G P,Q,R =      H     ##STR48##      H H      ##STR49##      H 1  106 S = G P,Q,R =      H     ##STR50##      H H (CH.sub.2).sub.10 CH.sub.3 H 1  107 P = H Q,R = CH.sub.3 S = G      ##STR51##      H H      ##STR52##      H 1  108 P = H Q,R = CH.sub.3 S =      G     ##STR53##      H H      ##STR54##      H 1  109 P = H Q,R = CH.sub.3 S =      G     ##STR55##      H H      ##STR56##      H 1  110 P,Q = H R = CH.sub.3 S =      G CH.sub.3 H H     ##STR57##      ##STR58##      1  111 P,R = CH.sub.3 Q = H S =      G     ##STR59##      CH.sub.3 CH.sub.3 (CH.sub.2).sub.10 CH.sub.3 H 1  112 P,Q = H R =     O(CH.sub.2).sub.9 CH.sub.3 S = G CH.sub.3 CH.sub.3 CH.sub.3 CH.sub.3 H 1      113 P,R = CH.sub.3, Q = G S =      H CH.sub.3 H H     ##STR60##      H 1  114 Q = OCH.sub.3 R = G P,S = H CH.sub.2      CH.sub.3 H H     ##STR61##      H 1      Compound No. R˜S R.sub.4 R.sub.1 n      201 R,Q = H R = O(CH.sub.2).sub.9 CH.sub.3 S =      G CH.sub.3     ##STR62##      0  202 P = H Q,R = CH.sub.3 S =      G     ##STR63##      ##STR64##      0  203 P,R = CH.sub.3 Q = O(CH.sub.2).sub.3 CH.sub.3S =      G     ##STR65##      ##STR66##      0  204 P,R = CH.sub.3 Q = G S =      H CH.sub.3     ##STR67##      0  205 P,R = CH.sub.3 Q = OH S =      G CH.sub.3     ##STR68##      0        Compound No. P˜S R.sub.4 R.sub.9 * R.sub.10      * R.sub.11 n           206 S = G P,Q,R =      H     ##STR69##      H H (CH.sub.2).sub.13 CH.sub.3 0        207 S = G P,Q,R =      H     ##STR70##      ##STR71##      (CH.sub.2).sub.9 CH.sub.3 0  208 S = G P,Q,R =      H CH.sub.3 H H (CH.sub.2).sub.13 CH.sub.3 0        209 S = G P,Q,R = H     CH.sub.3      ##STR72##      (CH.sub.2).sub.9 CH.sub.3 0         210 S = G P,Q,R =      H     ##STR73##      H H (CH.sub.2).sub.13 CH.sub.3 0        211 S = G P,Q,R =      H     ##STR74##      ##STR75##      (CH.sub.2).sub.9 CH.sub.3 0         212 P = H Q,R = CH.sub.3 S = G      ##STR76##      CH.sub.3 CH.sub.3      ##STR77##      0        213 P = H Q,R = CH.sub.3 S =      G     ##STR78##      ##STR79##      (CH.sub.2).sub.9 CH.sub.3 0  214 P = H Q,R = CH.sub.3 S = G CH.sub.3     CH.sub.3 CH.sub.3 (CH.sub.2).sub.9      CH.sub.3 0                              Compound No. P˜S R.sub.4     R.sub.9 R.sub.10 R.sub.11 n        215 P = H Q,R = CH.sub.3 S =      G CH.sub.3 CH.sub.3 CH.sub.3     ##STR80##      0  216 P = H Q,R = CH.sub.3 S =      G CH.sub.3 CH.sub.3 CH.sub.3     ##STR81##      0  217 P = H Q,R = CH.sub.3 S =      G     ##STR82##      CH.sub.3 CH.sub.3      ##STR83##      0  218 P = H Q,R = CH.sub.3 S = G (CH.sub.2).sub.8 CH.sub.3 CH.sub.3     CH.sub.3 CH.sub.3 0  219 P = H Q,R = CH.sub.3 S =      G     ##STR84##      CH.sub.3 CH.sub.3 CH.sub.3 0  220 P = NO.sub.2 Q,R = CH.sub.3 S = G     CH.sub.3 CH.sub.3 CH.sub.3 (CH.sub.2).sub.9 CH.sub.3 0  221 P =      N(CH.sub.3).sub.2 Q,R = CH.sub.3 S = G CH.sub.3 CH.sub.3 CH.sub.3     (CH.sub.2).sub.9 CH.sub.3 0  222 P = H R = OCH.sub.3 S = G CH.sub.3     CH.sub.3 CH.sub.3      ##STR85##      0  223 P,R = CH.sub.3 Q = H S =      G CH.sub.3 CH.sub.3 CH.sub.3 (CH.sub.2).sub.9 CH.sub.3 0  224 P,R =     CH.sub.3 Q = Cl S =      G CH.sub.3 CH.sub.3 CH.sub.3     ##STR86##      0  225 P,R = CH.sub.3 Q = N(CH.sub.3).sub.2 S = G CH.sub.3 CH.sub.3     CH.sub.3 (CH.sub.2).sub.9 CH.sub.3 0  226 P,R = CH.sub.3 Q = NH.sub.2 S     = G CH.sub.3 CH.sub.3 CH.sub.3 (CH.sub.2).sub.9 CH.sub.3 0  227 P,R =     CH.sub.3 Q = NHCOCH.sub.3 S =      G CH.sub.3 CH.sub.3 CH.sub.3     ##STR87##      0  228 P,R = H Q = CN S =      G     ##STR88##      CH.sub.3 CH.sub.3      ##STR89##      0        229 P = G Q,R = CH.sub.3 S =      H CH.sub.3     ##STR90##      ##STR91##      0  230 P,R = CH.sub.3 Q = G S =      H CH.sub.3 CH.sub.3 CH.sub.3 (CH.sub.2).sub.9 CH.sub.3 0  231 P,S =     CH.sub.3 Q = OCH.sub.3 R =      G     ##STR92##      CH.sub.3 CH.sub.3      ##STR93##      0  232 P,R = CH.sub.3 Q = G S = H (CH.sub.2).sub.8 CH.sub.3 CH.sub.3     CH.sub.3 CH.sub.3 0  233 P,R = H Q = COCH.sub.3 S =      G     ##STR94##      H H      ##STR95##      0  234 P,S = H Q = O(CH.sub.2).sub.9 CH.sub.3 R =      G     ##STR96##      CH.sub.3 CH.sub.3 CH.sub.3 0      ##STR97##       Compound No. P˜S R.sub.5      ˜R.sub.8 R.sub.1 R.sub.2 n           301 P,Q = H R =      O(CH.sub.2).sub.9 CH.sub.3 S = G R.sub.5,R.sub.6 = HR.sub.7,R.sub.8 =     CH.sub.3      ##STR98##      H 1  302 P,R = CH.sub.3 Q = NHCO(CH.sub.2).sub.8 CH.sub.3 S =  G     R.sub.5,R.sub.6 = HR.sub.7,R.sub.8 =      CH.sub.3     ##STR99##      H 1  303 P,R = CH.sub.3 Q = G S = NH(CH.sub.2).sub.9      CH.sub.3 R.sub.5,R.sub.6 = HR.sub.7,R.sub.8 =      CH.sub.3     ##STR100##      H 1  304 P = G R = H Q,S = CH.sub.3 R.sub.5,R.sub.6,R.sub.7,R.sub.8 = H      ##STR101##      H 1  305 P,R = CH.sub.3 Q = H S = G R.sub.5,R.sub.6 = HR.sub.7,R.sub.8     =      CH.sub.3     ##STR102##      H 1  306 P,S = H Q = G R = CH.sub.3 R.sub.5,R.sub.6 = HR.sub.7,R.sub.8     =      CH.sub.3     ##STR103##      H 1  307 P,Q = H R = CH.sub.3 S = G R.sub.5,R.sub.6 = HR.sub.7,R.sub.8     =      CH.sub.3     ##STR104##      H 1        Compound No. P˜S R.sub.5 ˜R.sub.8 R.sub.9 R.sub.10     R.sub.11 R.sub.2 n        308 P,Q = H R = CH.sub.3 S = G R.sub.5,R.sub.6 = HR.sub.7,R.sub.8 =     CH.sub.3 H H (CH.sub.2).sub.10 CH.sub.3 H 1  309 P,Q = H R = CH.sub.3 S     = G R.sub.5,R.sub.6 = HR.sub.7,R.sub.8 =      CH.sub.3 H H     ##STR105##      H 1  310 P,S = H Q = G R = CH.sub.3 R.sub.5,R.sub.6 = HR.sub.7,R.sub.8     = CH.sub.3 H H (CH.sub.2).sub.10 CH.sub.3 H 1  311 P,S = H Q = G R =     CH.sub.3 R.sub.5,R.sub.6 = HR.sub.7,R.sub.8 =      CH.sub.3 H H     ##STR106##      H 1  312 P,R = CH.sub.3 Q = H S = G R.sub.5,R.sub.6 = HR.sub.7,R.sub.8     =      CH.sub.3 H H     ##STR107##      H 1   313 P,R = CH.sub.3 Q = N(CH.sub.3).sub.2 S = G R.sub.5,R.sub.6 =  R     H.sub.7,R.sub.8 =      CH.sub.3 H H     ##STR108##      H 1  314 P,R = CH.sub.3 Q = Cl S = G R.sub.5,R.sub.6 = HR.sub.7,R.sub.8     =      CH.sub.3 H H     ##STR109##      ##STR110##      1  315 P,R = CH.sub.3 Q = H S = G R.sub.5,R.sub.6 = HR.sub.7,R.sub.8 =     CH.sub.3 H H      ##STR111##      H 1  316 P,R = CH.sub.3 Q = H S = G R.sub.5,R.sub.6,R.sub.8 = HR.sub.7     = (CH.sub.2).sub.9      CH.sub. 3 H H     ##STR112##      H 1  317 P,R = CH.sub.3 Q = G S = NHCOCH.sub.3 R.sub.5,R.sub.6 =     HR.sub.7,R.sub.8 =      CH.sub.3 CH.sub.3 H     ##STR113##      H 1  318 R = H Q,S = CH(CH.sub.3).sub.2R = G R.sub.5,R.sub.6 =      HR.sub.7,R.sub.8 = CH.sub.3 CH.sub.3 CH.sub.3 CH.sub.3 H 1  319 P,R =     CH.sub.3 Q = G S = N(CH.sub.3).sub.2 R.sub.5,R.sub.6 = HR.sub.7,R.sub.8     =      CH.sub.3 H H     ##STR114##      H 1        Compound No. P˜S R.sub.5      ˜R.sub.8 R.sub.1 n                  401 P,R = CH.sub.3 Q = H S =     G R.sub.5,R.sub.6 = H R.sub.7 = CH.sub.3R.sub.8 = (CH.sub.2).sub.8     CH.sub.3      ##STR115##      0  402 P,R = CH.sub.3 Q = H S = G R.sub.5,R.sub.6 = H R.sub.7,R.sub.8 =     CH.sub.3      ##STR116##      0  403 P,R = CH.sub.3 Q = H S = G R.sub.5,R.sub.6 = H R.sub.7,R.sub.8 =     CH.sub.3      ##STR117##      0  404 P,R = CH.sub.3 Q = H S = G R.sub.5,R.sub.6 = H R.sub.7,R.sub.8 =     CH.sub.3      ##STR118##      0  405 P,R = CH.sub.3 Q = H S = G R.sub.5,R.sub.6 = H R.sub.7,R.sub.8 =     CH.sub.3      ##STR119##      0  406 P,R = CH.sub.3 Q = H S = G R.sub.5,R.sub.6 = H R.sub.7,R.sub.8 =     CH.sub.3      ##STR120##      0  407 P,R = CH.sub.3 Q = H S = G R.sub.5,R.sub.6 = H R.sub.7,R.sub.8 =     CH.sub.3      ##STR121##      0  408 P,R = CH.sub.3 Q = H S = G R.sub.5,R.sub.6 = H R.sub.7,R.sub.8 =     CH.sub.3      ##STR122##      0  409 P,R = CH.sub.3 Q = H S = G R.sub.5,R.sub.6 = H R.sub.7,R.sub.8 =     CH.sub.3      ##STR123##      0  410 P,R = CH.sub.3 Q = H S = G R.sub.5,R.sub.6 = H R.sub.7,R.sub.8 =     CH.sub.3      ##STR124##      0  411 P,R = CH.sub.3 Q = H S = G R.sub.5,R.sub.6 = H R.sub.7,R.sub.8 =     CH.sub.3      ##STR125##      0  412 P,R = CH.sub.3 Q = H S = G R.sub.5,R.sub.6 = H R.sub.7,R.sub.8 =     CH.sub.3      ##STR126##      0  413 P,R = CH.sub.3 Q = H S = G R.sub.5,R.sub.6 = H R.sub.7,R.sub.8 =     CH.sub.3      ##STR127##      0  414 P,R = CH.sub.3 Q = N(CH.sub.3).sub.2S = G R.sub.5,R.sub.6 = H     R.sub.7,R.sub.8 =      CH.sub.3     ##STR128##      0  415 P,R = CH.sub.3 Q = N(CH.sub.3).sub.2S = G R.sub.5,R.sub.6 = H     R.sub.7,R.sub.8 =      CH.sub.3     ##STR129##      0  416 P,R = CH.sub.3 Q = N(CH.sub.3).sub.2S = G R.sub.5,R.sub.6 = H     R.sub.7,R.sub.8 =      CH.sub.3     ##STR130##      0  417 P,R = CH.sub.3 Q = N(CH.sub.3).sub.2S = G R.sub.5,R.sub.6 = H     R.sub.7,R.sub.8 =      CH.sub.3     ##STR131##      0  418 P,R = CH.sub.3 Q = N(CH.sub.3).sub.2S = G R.sub.5,R.sub.6 = H     R.sub.7,R.sub.8 =      CH.sub.3     ##STR132##      0  419 P,R = CH.sub.3 Q =  NHCOCH.sub.3 S = G R.sub.5,R.sub.6 = H     R.sub.7,R.sub.8 =      CH.sub.3     ##STR133##      0  420 P,R = CH.sub.3 Q = NH(CH.sub.2).sub.9 CH.sub.3 S =      G R.sub.5,R.sub.6 = H R.sub.7,R.sub.8 =      CH.sub.3     ##STR134##      0  421 P,R = CH.sub.3 Q = NHCO(CH.sub.2).sub.10 CH.sub.3 S =      G R.sub.5,R.sub.6 = H R.sub.7,R.sub.8 =      CH.sub.3     ##STR135##      0  422 P,R = CH.sub.3 S = GQ = NHCOC(CH.sub.3).sub.2 (CH.sub.2).sub.9     CH.sub.3 R.sub.5,R.sub.6 = H R.sub.7,R.sub.8 =      CH.sub.3     ##STR136##      0  423 P,R = CH.sub.3 Q = GS = NHCOC(CH.sub.3).sub.3 R.sub.5,R.sub.6 =     H R.sub.7,R.sub.8 =      CH.sub.3     ##STR137##      0  424 P,R = CH.sub.3 Q = OH S = G R.sub.5,R.sub.6 = H R.sub.7,R.sub.8     =      CH.sub.3     ##STR138##      0      425     ##STR139##      R.sub.5,R.sub.6 = H R.sub.7,R.sub.8 =      CH.sub.3     ##STR140##      0  426 Q,S = CH.sub.3 R = G P = H R.sub.5,R.sub.6 =  H R.sub.7 R.sub.8     =      CH.sub.3     ##STR141##      0        Compound No. P˜S R.sub.5 ˜R.sub.8 R.sub.9 R.sub.10     R.sub.11 n       427 P,Q,R = H S = G R.sub.5,R.sub.6 = H R.sub.7,R.sub.8 = CH.sub.3 H H (     CH.sub.2).sub.13 CH.sub.3 0        428 P,Q,R = H S = G R.sub.5,R.sub.6 =     H R.sub.7,R.sub.8 =      CH.sub.3     ##STR142##      (CH.sub.2).sub.9 CH.sub.3 0  429 P,Q = H R = CH.sub.3 = S =      G R.sub.5,R.sub.6 = H R.sub.7,R.sub.8 = CH.sub.3 H H (CH.sub.2).sub.13     CH.sub.3 0        430 P,Q = H R = CH.sub.3 S = G R.sub.5,R.sub.6 = H     R.sub.7,R.sub.8 =      CH.sub.3     ##STR143##      (CH.sub.2).sub.9 CH.sub.3 0  431 P,Q = H R = CH.sub.3 S =      G R.sub.5,R.sub.6 = H R.sub.7,R.sub.8 = CH.sub.3 CH.sub.3 CH.sub.3      ##STR144##      0  432 P,R = CH.sub.3 Q = H S = G R.sub.5,R.sub.6 = H R.sub.7,R.sub.8 =     CH.sub.3 CH.sub.3 CH.sub.3      ##STR145##      0  433 P,R = CH.sub.3 Q = H S = G R.sub.5,R.sub.6 = H R.sub.7 ,R.sub.8     =      CH.sub.3 CH.sub.3 Ch.sub.3     ##STR146##      0  434 P,R = CH.sub.3 Q = H S = G R.sub.5,R.sub.6 = H R.sub.7,R.sub.8 =     CH.sub.3 CH.sub.3 CH.sub.3      ##STR147##      0  435 P,R = CH.sub.3 Q = H S = G R.sub.5,R.sub.6 = H R.sub.7,R.sub.8 =     CH.sub.3 CH.sub.3 CH.sub.3      ##STR148##      0  436 P,R = CH.sub.3 Q = H S = G R.sub.5,R.sub.6 = H R.sub.7,R.sub.8 =     CH.sub.3 CH.sub.3 CH.sub.3      ##STR149##      0  437 P,R = CH.sub.3 Q = H S = G R.sub.5,R.sub.6 = H R.sub.7,R.sub.8 =     CH.sub.3 CH.sub.3  CH.sub.3      ##STR150##      0  438 P,R = CH.sub.3 Q = H S = G R.sub.5,R.sub.6 = H R.sub.7,R.sub.8 =     CH.sub.3 CH.sub.3 CH.sub.3      ##STR151##      0  439 P,R = CH.sub.3 Q = H S = G R.sub.5,R.sub.6 = H R.sub.7,R.sub.8 =     CH.sub.3 CH.sub.3 CH.sub.3      ##STR152##      0  440 P,R = CH.sub.3 Q = H S = G R.sub.5,R.sub.6 = H R.sub.7,R.sub.8 =     CH.sub.3 CH.sub.3 CH.sub.3      ##STR153##      0  441 P,R = CH.sub.3 Q = H S = G R.sub.5,R.sub.6 = H R.sub.7,R.sub.8 =     CH.sub.3 CH.sub.3 CH.sub.3      ##STR154##      0  442 P,R = CH.sub.3 Q = H S = G R.sub.5,R.sub.6 = H R.sub.7,R.sub.8 =     CH.sub.3 CH.sub.3 CH.sub.3      ##STR155##      0  443 P,R = CH.sub.3 Q = H S = G R.sub.5,R.sub.6 = H R.sub.7,R.sub.8 =     CH.sub.3 CH.sub.3 CH.sub.3      ##STR156##      0  444 P,R = CH.sub.3 Q = H S = G R.sub.5,R.sub.6 = H R.sub.7,R.sub.8 =     CH.sub.3 CH.sub.3 CH.sub.3      ##STR157##      0  445 P,R = CH.sub.3 Q = H S = G R.sub.5,R.sub.6 = H R.sub.7,R.sub.8 =     CH.sub.3 CH.sub.3 CH.sub.3      ##STR158##      0  446 P,R = CH.sub.3 Q = H S = G R.sub.5,R.sub.6 = H R.sub.7,R.sub.8 =     CH.sub.3 CH.sub.3 CH.sub.3      ##STR159##      0  447 P,R = CH.sub.3 Q = H S = G R.sub.5,R.sub.6 = H R.sub.7,R.sub.8 =     CH.sub.3 CH.sub.3 CH.sub.3      ##STR160##      0         448 P,R = CH.sub.3 Q = H S = G R.sub.5,R.sub.6 =      H R.sub.7,R.sub.8 =      CH.sub.3 CH.sub.3 CH.sub.3     ##STR161##      0  449 P,R = CH.sub.3 Q = H S = G R.sub.5,R.sub.6 =  H R.sub.7,R.sub.8     =      CH.sub.3 CH.sub.3 CH.sub.3     ##STR162##      0  450 P,R = CH.sub.3 Q = H S = G R.sub.5,R.sub.6 = H R.sub.7,R.sub.8 =     CH.sub.3 CH.sub.3 CH.sub.3      ##STR163##      0  451 P,R = CH.sub.3 Q = H S = G R.sub.5,R.sub.6 = H R.sub.7,R.sub.8 =     CH.sub.3 CH.sub.3 CH.sub.3      ##STR164##      0  452 P,R = CH.sub.3 Q = H S = G R.sub.5,R.sub.6 = H R.sub.7,R.sub.8 =     CH.sub.3 CH.sub.3 CH.sub.3      ##STR165##      0  453 P,R = CH.sub.3 Q = H S = G R.sub.5 ,R.sub.6 = H R.sub.7,R.sub.8     =      CH.sub.3 CH.sub.3 CH.sub.3     ##STR166##      0  454 P,R = CH.sub.3 Q = H S = G R.sub.5,R.sub.6 = H R.sub.7,R.sub.8 =     CH.sub.3 CH.sub.3 CH.sub.3      ##STR167##      0  455 P,R = CH.sub.3 Q = H S = G R.sub.5,R.sub.6 = H R.sub.7,R.sub.8 =     CH.sub.3 CH.sub.3 CH.sub.3      ##STR168##      0  456 P,R = CH.sub.3 Q = H S = G R.sub.5,R.sub.6 = H R.sub.7,R.sub.8 =     CH.sub.3 CH.sub.3 CH.sub.3      ##STR169##      0  457 P,R = CH.sub.3 Q = H S = G R.sub.5,R.sub.6 = H R.sub.7,R.sub.8 =     CH.sub.3 CH.sub.3 CH.sub.3      ##STR170##      0  458 P,R = CH.sub.3 Q = H S = G R.sub.5,R.sub.6 = H R.sub.7,R.sub.8 =     CH.sub.3 CH.sub.3 CH.sub.3      ##STR171##      0  459 P,R = CH.sub.3 Q = H S = G R.sub.5,R.sub.6 = H R.sub.7,R.sub.8 =     CH.sub.3 CH.sub.3 CH.sub.3      ##STR172##      0  460 P,R = CH.sub.3 Q = H S = G R.sub.5,R.sub.6  = H R.sub.7,R.sub.8     =      CH.sub.3 CH.sub.3 CH.sub.3     ##STR173##      0  461 P,R = CH.sub.3 Q = H S = G R.sub.5,R.sub.6 = H R.sub.7,R.sub.8 =     CH.sub.3 CH.sub.3 CH.sub.3      ##STR174##      0  462 P,R = CH.sub.3 Q = H S = G R.sub.5,R.sub.6 = H R.sub.7,R.sub.8 =     CH.sub.3 CH.sub.3 CH.sub.3      ##STR175##      0  463 P,R = CH.sub.3 Q = H S = G R.sub.5,R.sub.6 = H R.sub.7,R.sub.8 =     CH.sub.3 CH.sub.3 CH.sub.3      ##STR176##      0  464 P,R = CH.sub.3 Q = H S = G R.sub.5,R.sub.6 = H R.sub.7,R.sub.8 =     CH.sub.3 CH.sub.3 CH.sub.3      ##STR177##      0  465 P,R = CH.sub.3 Q = H S = G R.sub.5,R.sub.6 = H R.sub.7,R.sub.8 =     CH.sub.3 CH.sub.3 CH.sub.3      ##STR178##      0  466 P,R = CH.sub.3 Q = H S = G R.sub.5,R.sub.6 = H R.sub.7,R.sub.8 =     CH.sub.3 CH.sub.3 CH.sub.3      ##STR179##      0  467 P,R = CH.sub.3 Q = H S =  G R.sub.5,R.sub.6 = H R.sub.7,R.sub.8     =      CH.sub.3 CH.sub.3 CH.sub.3     ##STR180##      0  468 P,R = CH.sub.3 Q = H S = G R.sub.5,R.sub.6 = H R.sub.7,R.sub.8 =     CH.sub.3 CH.sub.3 CH.sub.3      ##STR181##      0  469 P,R = CH.sub.3 Q = H S = G R.sub.5,R.sub.6 = H R.sub.7,R.sub.8 =     CH.sub.3 CH.sub.3 CH.sub.3      ##STR182##      0  470 P,R = CH.sub.3 Q = H S = G R.sub.5,R.sub.6 = H R.sub.7,R.sub.8 =     CH.sub.3 CH.sub.3 CH.sub.3      ##STR183##      0  471 P,R = CH.sub.3 Q = H S = G R.sub.5,R.sub.6 = H R.sub.7,R.sub.8 =     CH.sub.3 CH.sub.3 CH.sub.3      ##STR184##      0  472 P,R = CH.sub.3 Q = H S = G R.sub.5,R.sub.6 = H R.sub.7,R.sub.8 =     CH.sub.3 CH.sub.3 CH.sub.3      ##STR185##      0  473 P,R = CH.sub.3 Q = H S = G R.sub.5,R.sub.6 = H R.sub.7,R.sub.8 =     CH.sub.3 CH.sub.3 CH.sub.3      ##STR186##      0  474 P,R =  CH.sub.3 Q = H S = G R.sub.5,R.sub.6 = H R.sub.7,R.sub.8     =      CH.sub.3 CH.sub.3 CH.sub.3     ##STR187##      0  475 P,R = CH.sub.3 Q = H S = G R.sub.5,R.sub.6 = H R.sub.7,R.sub.8 =     CH.sub.3 CH.sub.3 CH.sub.3      ##STR188##      0  476 P,R = CH.sub.3 Q = H S = G R.sub.5,R.sub.6 = H R.sub.7,R.sub.8 =     CH.sub.3 CH.sub.3 CH.sub.3      ##STR189##      0  477 P,R = CH.sub.3 Q = H S = G R.sub.5,R.sub.6 = H R.sub.7,R.sub.8 =      CH.sub.3 CH.sub.3 CH.sub.3      ##STR190##      0  478 P,R = CH.sub.3 Q = H S = G R.sub.5,R.sub.6 = H R.sub.7,R.sub.8 =     CH.sub.3 CH.sub.3 CH.sub.3      ##STR191##      0  479 P,R = CH.sub.3 Q = H S = G R.sub.5,R.sub.6 = H R.sub.7,R.sub.8 =     CH.sub.3 H H      ##STR192##      0  480 P,R = CH.sub.3 Q = H S = G R.sub.5,R.sub.6 = H R.sub.7,R.sub.8 =     CH.sub.3 H H (CH.sub.2).sub.13 CH.sub.3 0         481 P,R = CH.sub.3 Q =     H S = G R.sub.5,R.sub.6 = H R.sub.7,R.sub.8 =      CH.sub.3     ##STR193##      (CH.sub.2).sub.9 CH.sub.3 0  482 P,R = CH.sub.3 Q = Cl S =      G R.sub.5,R.sub.6 = H R.sub.7,R.sub.8 = CH.sub.3 H H (CH.sub.2).sub.13     CH.sub.3 0        483 P,R = CH.sub.3 Q = Cl S = G R.sub.5,R.sub.6 = H     R.sub.7,R.sub.8 =      CH.sub.3     ##STR194##      (CH.sub.2).sub.9 CH.sub.3 0  484 P,R = CH.sub.3 Q = Cl S =      G R.sub.5,R.sub.6 = H R.sub.7,R.sub.8  = CH.sub.3 CH.sub.3 CH.sub.3     (CH.sub.2).sub.9 CH.sub.3 0 485 P,R = CH.sub.3 Q = NO.sub.2 S = G     R.sub.5,R.sub.6 = H R.sub.7,R.sub.8 = CH.sub.3 CH.sub.3 CH.sub.3     (CH.sub.2).sub.9 CH.sub.3 0 486 P,R = CH.sub.3 Q = NH.sub.2 S = G     R.sub.5,R.sub.6 = H R.sub.7,R.sub.8 = CH.sub.3 CH.sub.3 CH.sub.3     (CH.sub.2).sub.9 CH.sub.3 0 487 P,R = CH.sub.3 Q = OH S =      G R.sub.5,R.sub.6 = H R.sub.7,R.sub.8 = CH.sub.3 CH.sub.3 CH.sub.3     (CH.sub.2).sub.9 CH.sub.3 0 488 P,R = CH.sub.3 Q = NHCOCH.sub.3 S = G     R.sub.5,R.sub.6 = H R.sub.7,R.sub.8 = CH.sub.3 CH.sub. 3 CH.sub.3     (CH.sub.2).sub.9 CH.sub.3 0 489 P,R = CH.sub.3 Q = NHCH.sub.3 S = G     R.sub.5,R.sub.6 = H R.sub.7,R.sub.8 = CH.sub.3 CH.sub.3 CH.sub.3     (CH.sub.2).sub.9 CH.sub.3 0 490 P,R = CH.sub.3 Q = N(CH.sub.3).sub.2 S =     G R.sub.5,R.sub.6 = H R.sub.7,R.sub.8 = CH.sub.3 CH.sub.3 CH.sub.3     (CH.sub.2).sub.9 CH.sub.3 0  491 P,R = CH.sub.3 Q = N(CH.sub.3).sub.2 S     = G R.sub.5,R.sub.6 = H R.sub.7,R.sub.8 = CH.sub.3 CH.sub.3 CH.sub.3      ##STR195##      0  492 P,R = CH.sub.3 Q = N(CH.sub.3).sub.2 S = G R.sub.5,R.sub.6 = H     R.sub.7 ,R.sub.8 = CH.sub.3 H H (CH.sub.2).sub.7 CHCH(CH.sub.2).sub.7     CH.sub.3 0        493 P,R = CH.sub.3 Q = N(CH.sub.3).sub.2 S = G     R.sub.5,R.sub.6 = H R.sub.7,R.sub.8 =      CH.sub.3     ##STR196##      ##STR197##      0  494 P,R = CH.sub.3 S = G R.sub.5,R.sub.6 = H R.sub.7,R.sub.8 =     CH.sub.3 CH.sub.3 CH.sub.3 (CH.sub.2).sub.9 CH.sub.3 0  Q =      NHCOC(CH.sub.3).sub.2 (CH.sub.2).sub.9 CH.sub.3 495 P,R= CH.sub.3 S = G     R.sub.5,R.sub.6 = H R.sub.7,R.sub.8 = CH.sub.3 CH.sub.3 CH.sub.3     CH.sub.3 0  Q =  NHCOC(CH.sub.3).sub.2 (CH.sub.2).sub.9 CH.sub.3 496 P,R     = CH.sub.3 S = G R.sub.5,R.sub.6 = H R.sub.7,R.sub.8 = CH.sub.3 CH.sub.3 C     H.sub.3 CH.sub.3 0  Q = NHCO(CH.sub.2).sub.10 CH.sub.3 497 P,R =     CH.sub.3 S = G R.sub.5,R.sub.6 = H R.sub.7,R.sub.8 = CH.sub.3 CH.sub.3     CH.sub.3 CH.sub.3 0  Q = NH(CH.sub.2).sub.9 CH.sub.3 498 P,R = CH.sub.3     S = GQ = NHCOC(CH.sub.3).sub.2 (CH.sub.2).sub.3 CH.sub.3 R.sub.5,R.sub.6     = H R.sub.7,R.sub.8 =      CH.sub.3 CH.sub.3 CH.sub.3     ##STR198##      0  499 P = H Q = NHCO(CH.sub.2).sub.10 CH.sub.3 R.sub.5,R.sub.6 = H     R.sub.7,R.sub.8 = CH.sub.3 H H (CH.sub. 2).sub.10 CH.sub.3 0  R =     CH.sub.3 S = G 500 P = H Q = NHCO(CH.sub.2).sub.8      CH.sub.3 R.sub.5,R.sub.6 = H R.sub.7,R.sub.8 = CH.sub.3 CH.sub.3     CH.sub.3 CH.sub.3 0  R = CH.sub.3 S = G 501 P = H Q =      NHCOC(CH.sub.3).sub.2 (CH.sub.2).sub.9 CH.sub.3 R.sub.5,R.sub.6 = H     R.sub.7,R.sub.8 = CH.sub.3 CH.sub.3 CH.sub.3 (CH.sub.2).sub.9 CH.sub.3 0      R = CH.sub.3 S = G 502 P,Q = H R = OCH.sub.3 S = G R.sub.5,R.sub.6 = H     R.sub.7,R.sub.8 = CH.sub.3 CH.sub.3 CH.sub.3 (CH.sub.2).sub.9 CH.sub.3 0     503 P,Q = H R = O(CH.sub.2).sub.9 CH.sub.3 S = G R.sub.5,R.sub.6 =  H     R.sub.7,R.sub.8 = CH.sub.3 CH.sub.3 CH.sub.3 (CH.sub.2).sub.9 CH.sub.3 0     504 P = CH.sub.3 Q = H R = OCH.sub.3 S = G R.sub.5,R.sub.6 =      H R.sub.7,R.sub.8 = CH.sub.3 CH.sub.3 CH.sub.3 (CH.sub.2).sub.9     CH.sub.3 0 505 P,Q = H R = O(CH.sub.2).sub.9 CH.sub.3 S =      G R.sub.5,R.sub.6 = H R.sub.7,R.sub.8 = CH.sub.3 CH.sub.3 CH.sub.3     CH.sub.3 0      506     ##STR199##      R.sub.5,R.sub.6 = H R.sub.7,R.sub.8 = CH.sub.3 CH.sub.3 H CH.sub.3 0     507 P = H Q = COCH.sub.3 R = OCH.sub.3 S =  G R.sub.5,R.sub.6 = H     R.sub.7,R.sub.8 = CH.sub.3 CH.sub.3 CH.sub.3 (CH.sub.2).sub.9 CH.sub.3 0      508 P = H Q = COCH.sub.3 R = OCH.sub.3 S = G R.sub.5,R.sub.6 = H     R.sub.7,R.sub.8 =      CH.sub.3 CH.sub.3 CH.sub.3     ##STR200##      0 509 P = H Q = CH.sub.2 CH.sub.3 R = OCH.sub.3 S = G R.sub.5,R.sub.6 =     H R.sub.7,R.sub.8 = CH.sub.3 CH.sub.3 CH.sub.3 (CH.sub.2).sub.9 CH.sub.3     0 510 P = H Q = COCH.sub.2 S = G R.sub.5,R.sub.6 = H R.sub.7,R.sub.8 =     CH.sub.3 CH.sub.3 CH.sub.3 CH.sub.3 0  R = O(CH.sub.2).sub.9 CH.sub.3     511 P = H Q = CO(CH.sub.2).sub.10 CH.sub.3 R.sub.5,R.sub.6 =      H R.sub.7,R.sub.8 = CH.sub.3 CH.sub.3 CH.sub.3 CH.sub.3 0  R =      OCH.sub.3 S = G 512 P = H Q = NO.sub.2 R = OCH.sub.3 S =      G R.sub.5,R.sub.6 = H R.sub.7,R.sub.8 = CH.sub.3 CH.sub.3 CH.sub.3     (CH.sub.2).sub.9 CH.sub.3 0 513 P = H Q = N(CH.sub.3).sub.2 S = G     R.sub.5,R.sub.6 = H R.sub.7,R.sub.8 = CH.sub.3 CH.sub.3 CH.sub.3     CH.sub.3 0  R = O(CH.sub.2).sub.9 CH.sub.3      514     ##STR201##      R.sub.5 ,R.sub.6 = H R.sub.7,R.sub.8 = CH.sub.3 CH.sub.3 CH.sub.3     CH.sub.3 0  515 P = H Q = N(CH.sub.3).sub.2 R =      OCH.sub.3 R.sub.5,R.sub.6 = H R.sub.7,R.sub.8 = CH.sub.3 CH.sub.3     CH.sub.3 (CH.sub.2).sub.9 CH.sub.3 0  S = G 516 P = H Q =      NHCOC(CH.sub.3).sub.3 S = G R.sub.5,R.sub.6 = H R.sub.7,R.sub.8 =     CH.sub.3 CH.sub.3 CH.sub.3 CH.sub.3 0  R = O(CH.sub.2).sub.9 CH.sub.3     517 P = H Q = N(CH.sub.3).sub.2 R = OCH.sub.3 S = G R.sub.5,R.sub.6 = H     R.sub.7,R.sub.8 =      CH.sub.3 CH.sub.3 CH.sub.3     ##STR202##      0  518 P,R = CH.sub.3 Q = OCOCH(CH.sub.3).sub.2 S = G R.sub.5,R.sub.6 =     H R.sub.7,R.sub.8 =      CH.sub.3 CH.sub.3 CH.sub.3     ##STR203##      0  519 P = H Q = OCH.sub.3 R = G S = CH.sub.3 R.sub.5,R.sub.6 = H     R.sub.7,R.sub.8 =      CH.sub.3 CH.sub.3 CH.sub.3     ##STR204##      0  520 P = N(CH.sub.3).sub.2 Q,S = CH.sub.3 R = G R.sub.5,R.sub.6 = H     R.sub.7,R.sub.8 = CH.sub.3 CH.sub.3 CH.sub.3 (CH.sub.2).sub.9 CH.sub.3 0      521 P,S = H Q = G R = CH.sub.3 R.sub.5,R.sub.6 = H R.sub.7,R.sub.8 =     CH.sub.3 H H (CH.sub.2).sub.13 CH.sub.3 0        522 P,S = H Q = G R =     CH.sub.3 R.sub.5,R.sub.6 = H R.sub.7,R.sub.8 =      CH.sub.3     ##STR205##      (CH.sub.2).sub.9 CH.sub.3 0  523 P,R = CH.sub.3 Q = G S =      N(CH.sub.3).sub.2 R.sub.5,R.sub.6 = H R.sub.7,R.sub.8 = CH.sub.3     CH.sub.3 CH.sub.3 (CH.sub.2).sub.9 CH.sub.3 0 524 P,R = CH.sub.3 Q = G S     = NHCOCH.sub.3 R.sub.5,R.sub.6 = H R.sub.7,R.sub.8 = CH.sub.3 CH.sub.3     CH.sub.3 (CH.sub.2).sub.9 CH.sub.3 0  525 P,R = CH.sub.3 S = H Q = G     R.sub.5,R.sub.6 = H R.sub.7,R.sub.8 = CH.sub.3 CH.sub.3 CH.sub.3      ##STR206##      0  526 P = G, Q = OCH.sub.3 R,S = H R.sub.5,R.sub.6 = H R.sub.7,R.sub.8     =      CH.sub.3 CH.sub.3 CH.sub.3     ##STR207##      0  527 P = G Q,S = CH.sub.3 R = H R.sub.5,R.sub.6 = H R.sub.7,R.sub.8 =     CH.sub.3 CH.sub.3 CH.sub.3 (CH.sub.2).sub.9 CH.sub.3 0 528 Q,R =     CH.sub.3 S = G P = H R.sub.5,R.sub.6 = CH.sub.3 R.sub.7,R.sub.8 = H     CH.sub.3 CH.sub.3 (CH.sub.2).sub.9 CH.sub.3 0 529 R = OCH.sub.3 S = G     P,Q = H R.sub.5,R.sub.6  = H R.sub.7,R.sub.8 = CH.sub.2 CH.sub.3     CH.sub.3 CH.sub.3 (CH.sub.2).sub.9 CH.sub.3 0 530 P,R = CH.sub.3 Q =     N(CH.sub.3).sub.2 S = G R.sub.5,R.sub.6,R.sub.7,R.sub.8 = H CH.sub.3     CH.sub.3 (CH.sub.2).sub.9 CH.sub.3 0 531 R = OCH.sub.3 S = G P,Q = H     R.sub.5,R.sub.6,R.sub.7 = H CH.sub.3 CH.sub.3 CH.sub.3 0   R.sub.8 =     (CH.sub.2).sub.9 CH.sub.3  532 P,R = CH.sub.3 Q = Cl S =      G R.sub.5,R.sub.6,R.sub.7,R.sub.8 =      H CH.sub.3 CH.sub.3     ##STR208##      0     When only one group is shown in these columns, the group formed by R.sub.     and R.sub.10, together, is shown (the same herein below).

The compounds having the above-mentioned formula (I) include some knowncompounds and novel compounds represented by the formula (Ia). The novelcompounds can also be produced according to production processes used inthe production of the known compounds. Preferably, they can be producedby a novel production process proposed as one aspect of the presentinvention.

For example, the compounds having the formula (I) can be produced by thefollowing respective reaction schemes. ##STR209## wherein R₁, R₂, R₃, Zand m are as defined above.

The reactions represented by the reaction schemes (i) and (ii) can bepracticed by reacting the corresponding amine compound represented bythe formula (III) or (IV) with an isocyanate compound represented by theformula (II) or (V) in the absence or presence of a solvent.

Most of the compounds represented by the formulae (II) to (VI) are knowncompounds and can be produced by known processes. The novel compoundscan be produced according to the processes for producing the knowncompounds. For example, 2,3-dihydrobenzofuranylamine which is a compoundbelonging to the compounds represented by the formula (IV) can beproduced a process described in Chem. Abst., 66, 463196 (1969).

In general, with respect to the amount ratio of reactants (startingcompounds) used in the reaction, the amount of the amine compound andthe amount of the isocyanate compound are preferably set so as to beequivalent to each other. However, the optimal amount ratio variesdepending upon the reactants used. A person having ordinary skill in theart can learn the optimal amount ratio through a simple small-scaleexperiment. In general, the amount of the isocyanate compound can bevaried in the range of from 0.2 to 5 equivalents based on one equivalentof the amine compound.

The reaction solvent may be any type of solvent so far as it has noadverse effect on the reaction. Examples of the solvent generally usedin the reaction include halogenated hydrocarbons, such asdichloromethane and chloroform, aromatic hydrocarbons, such as benzeneand toluene, ethers, such as diethyl ether and tetrahydrofuran, esters,such as ethyl acetate, and aprotic polar solvents, such asdimethylformamide and dimethylsulfoxide.

With respect to the reaction conditions, the reaction temperature is inthe range of from -20° to 150° C., preferably in the range of from roomtemperature to 100° C., and the reaction time is usually 72 hrs or less.

After the completion of the reaction, the reaction mixture may besubjected to conventional separation and purification procedure, thatis, extraction, recrystallization, chromatography, etc. to isolate anintended benzoxa condensed ring compound represented by the formula(I-b) or (I-c). Further, the product can be converted to apharmaceutically acceptable salt by a conventional method.

The reaction corresponding to the reaction scheme (iii) is a reaction ofan amine compound represented by the formula (IV) with a reactivederivative of a carboxylic acid represented by the formula (IV). Amongthe compounds represented by the formula (I), compounds belonging to theabove-mentioned amide derivatives can be efficiently produced by thisreaction.

This reaction can be practiced according to a known reaction of an aminocompound with a carboxylic acid or a reactive derivative of thecarboxylic acid. The reactive derivative of a carboxylic acid used inthe invention embraces all reactive derivatives of carboxylic acidsusually known in the field of organic synthesis including acidanhydrides, acid halides and mixed acid anhydrides of the correspondingcarboxylic acids.

Accordingly, the above-mentioned reaction can be practiced by reactingthe amine compound with 1 to 5 equivalents of the correspondingcarboxylic acid chloride or acid anhydride in the presence of a solvent.

The reaction temperature is in the range of from -20° to 150° C.,preferably in the range of from -10° to 100° C., and the reaction timeis usually 72 hrs or less.

Examples of the reaction solvent include halogenated hydrocarbons, suchas dichloromethane and chloroform, aromatic hydrocarbons, such asbenzene and toluene, ethers, such as diethyl ether and tetrahydrofuran,esters, such as ethyl acetate, and aprotic polar solvents, such asdimethylformamide and dimethylsulfoxide. In this case, 0.1 to 10equivalents of a basic amine compound, for example, triethylamine,pyridine or 4-dimethylaminopyridine, may be added to the reactionsystem.

After the completion of the reaction, the reaction mixture may besubjected to conventional separation and purification procedure, thatis, extraction, recrystallization, chromatography, etc. to isolate anintended benzoxa condensed ring compound represented by the formula(I-d).

As specifically mentioned above, the compound represented by the formula(I) or the compound represented by the formula (Ia) can bear, in itsmolecule, an amino group or a carboxyl group. Therefore, if necessary,these compounds can be converted to their acid addition salts or alkaliaddition salts by a conventional salt forming reaction.

For example, with respect to the compound bearing an amino grouprepresented by the formula (I), a salt forming reaction can be practicedby simply mixing the corresponding compound represented by the formula(I) with an inorganic acid or an organic acid in the absence or presenceof a suitable solvent. The inorganic acid or organic acid used in thesalt forming reaction may be any one so far as it can produce apharmaceutically acceptable salt upon being reacted with the compoundrepresented by the formula (I). Favorable examples of the inorganic acidor organic acid include mineral acids, such as hydrochloric acid,hydrobromic acid, sulfuric acid, phosphoric acid and carbonic acid, andorganic acids, such as citric acid, malic acid, oxalic acid, tartaricacid, fumaric acid and methanesulfonic acid.

The compound represented by the formula (I) and its pharmaceuticallyacceptable salt provided by the present invention have an ACAT enzymeinhibitory activity and an excellent pharmacological activity forlowering the total cholesterol and LDL levels of the blood, liver andarterial wall, which renders them useful for the suppression of theprogress or regression of hyperlipidemia and atherosclerosis.

The benzoxa condensed ring compound and its pharmaceutically acceptablesalt according to the present invention can be blended with apharmacologically acceptable carrier to provide a pharmaceuticalcomposition. Although the content of the active ingredient in thepharmaceutical composition is not particularly limited, it is usually inthe range of from 5 to 70% by weight.

The compound represented by the formula (I) and its pharmaceuticallyacceptable salt provided by the present invention can be orallyadministered.

Examples of dosage forms of the oral preparation include a tablet, apowder, granules and a capsule.

These dosage forms can be shaped according to a conventional methodthrough the use of, for example, an excipient, such as lactose, starchor crystalline cellulose, a binder, such as carboxymethylcellulose,methyl cellulose or polyvinyl pyrrolidone, and a disintegrator, such assodium alginate, sodium hydrogencarbonate or sodium laurate. The powderand granules as well can be shaped in a similar manner. The capsule canbe shaped by filling a capsule, such as gelatin, with a powder orgranules. Examples of parenteral preparations include percutaneouspreparations, such as a suppository, a patch and an injection.

Although the dose of the compound represented by the formula (I) and itspharmaceutically acceptable salt provided by the present inventionvaries depending upon the severity of disease, age and sex of patient,it is usually about 1 to 500 mg/day/adult.

EXAMPLES

The present invention will now be described in more detail withreference to, but is by no means limited to, the following Examples.

REFERENCE EXAMPLE 1 Synthesis of 2-amino-6-nitrophenol

100 ml of methanol was added to 5.0 g of 2,6-dinitrophenol in a vessel.The inside of the vessel was purged with argon. About 1.5 g of 10%palladium-carbon was added thereto, the inside of the vessel was purgedwith argon and then with hydrogen, and the reaction mixture was stirredat room temperature overnight.

After the completion of the reaction, the palladium-carbon was removedby filtration with Celite, and the filtrate was concentrated to provide4.1 g of the title compound, that is, 2-amino-6-nitrophenol.

¹ H NMR (CDCl₃) δ (ppm): 10.70 (s, 1H, OH), 7.46(dd, J=2.0Hz, 8.2Hz, 1H,ArH), 6.94(dd, J=2.0Hz, 7.7Hz, 1H, ArH), 6.76(dd, J=8.2Hz, 7.7Hz, 1H,ArH), 3.70-4.50(br, 2H, NH₂)

REFERENCE EXAMPLE 2 Preparation of trimethylsilyl polyphosphate solution(PPSE)

50 ml of 1,2-dichlorobenzene was added to 10 g of phosphorus pentaoxide,and 25 ml of hexamethyldisiloxane was added to the mixture withstirring. The mixture was allowed to react under reflux for 10 min andcooled to room temperature to prepare the title solution.

REFERENCE EXAMPLE 3 Synthesis of 7-nitro-2-(3-pyridyl)benzoxazole

15 ml of the trimethylsilyl polyphosphate solution prepared in ReferenceExample 2 was placed in a vessel purged with argon, and 1.06 g of2-amino-6-nitrophenol prepared in Reference Example 1 and 0.62 g ofnicotinic acid. The mixture was allowed to react under reflux for 3 hr.After the completion of the reaction, 50 ml of a 1N aqueous sodiumhydroxide solution was added to the reaction mixture. The intendedproduct was extracted with dichloromethane (50 ml×3), and the organiclayer was washed with water and then dried. The organic solvent wasremoved by evaporation, and the resultant concentrate was purified bysilica gel column chromatography (hexane:ethyl acetate=6:4) to provide0.49 g of the title compound.

¹ H NMR (CDCl₃) δ (ppm): 9.40(d, J=1.5Hz, 1H, ArH), 8.87(dd, J=4.8Hz,1.5Hz, 1H, ArH), 8.58(ddd, J=1.8Hz, 2.2Hz, 7.9Hz, 1H, ArH), 8.34 (dd,J=2.2Hz, 1.1Hz, 1H, ArH), 8.27 (d, J=1.1Hz, 1H, ArH), 7.58-8.24(m, 2H,ArH)

REFERENCE EXAMPLE 4 Synthesis of 7-amino-2-(3-pyridyl)benzoxazole

4 ml of 10% acetic acid was added to 7-nitro-2-(3-pyridyl)benzoxazoleprepared in Reference Example 3, and 200 mg of powdered iron was addedby portions with stirring at room temperature. The mixture was heated to100° C. in an oil bath and stirred for 2 hr. The reaction mixture wasfiltered through Celite and washed with a small amount of dilutehydrochloric acid. The filtrate was neutralized with an aqueous sodiumhydroxide solution, the product was extracted with ethyl acetate, andthe organic layer was dried. The organic solvent was removed byevaporation to provide 153 mg of the intended title compound.

¹ H NMR (δ/ppm, d₆ -DMSO) 9.37 (dd, J=0.9Hz, 2.2Hz, 1H, ArH), 8.78 (dd,J=1.8Hz, 4.8Hz, 1H, ArH), 8.59 (ddd, J=1.8Hz, 2.2Hz, 8.1Hz, 1H, ArH),7.63(ddd, J=0.9Hz, 4.8Hz, 8.1Hz, 1H, ArH), 6.92-7.10 (m, 2H, ArH), 6.67(dd, J=1.8Hz, 7.3Hz, 1H, ArH), 5.59(s, 2H, NH₂)

REFERENCE EXAMPLE 5 Synthesis of 2-phenylbenzoxazolyl-7-isocyanate

137 mg of 7-amino-2-phenylbenzoxazole was suspended in 5 ml of1,2-dichlorobenzene, and the mixture was stirred under reflux for 10min. The reaction mixture was somewhat cooled. 129 mg of triphosgene and132 mg of triethylamine were added thereto, and the mixture, as such,was stirred for 20 min.

After the completion of the reaction, the reaction mixture was filteredthrough Celite to remove insolubles. The solvent was removed byevaporation to provide 154 mg of the intended title compound.

EXAMPLE 1

Synthesis of1-(2-phenylbenzoxazol-7-yl)-3-[(1-phenylcyclopentyl)methyl]urea (105)##STR210##

A 77 mg amount of 2-phenylbenzoxazolyl-7-isocyanate prepared inReference Example 5 was dissolved in 3 ml of ethyl acetate, 57 mg of1-phenylcyclopentylmethylamine was added thereto, and the mixture wasstirred at room temperature overnight.

After the completion of the reaction, the solvent was removed byevaporation. The resultant precipitate was recrystallized fromhexane-ethyl acetate to provide 71 mg of the intended title compound.

¹ H NMR (CDCl₃) δ (ppm): 8.16-8.27(m, 2H, A/H), 7.44-7.59(m, 4H, ArH),7.13-7.41 (m, 9H, A/H), 6.35(s, 1H, NH), 4.49(br, 1H, NH), 3.47(d,J=5.7Hz, 2H, --CH₂ --), 1.70-2.10(br, 8H, --CH₂ --) m.p.: 214°-215° C.

EXAMPLE 2 Synthesis ofN-[2-(3-pyridyl)benzoxazol-7-yl]-1-decylcyclopentanecarboxamide (207)##STR211##

A 65 mg amount of 1-decylcyclopentanecarboxylic acid chloride was addedto a solution of 51 mg of 7-amino-2-(3-pyridyl)benzoxazole and 0.034 mlof triethylamine in 2.5 ml of dichloromethane, and the mixture wasstirred at room temperature for 9 hrs.

A saturated aqueous potassium hydrogensulfate solution (10 ml) was addedto the reaction mixture, and the mixture was extracted with ethylacetate (20 ml×2).

The extract was dried over anhydrous magnesium sulfate, filtered,concentrated and then purified by thin-layer chromatography(hexane:ethyl acetate=1:1) to provide 35 mg of the intended titlecompound.

Property Values: ¹ H NMR (CDCl₃) δ (ppm): 9.45(dd, J=2.2Hz, 0.7Hz, 1H,ArH), 8.79(dd, J=4.8Hz, 1.8Hz, 1H, ArH), 8.51 (ddd, J=7.9Hz, 2.2Hz,1.8Hz, 1H, ArH), 8.08 (dd, J=7.9Hz, 1.3Hz, 1H, ArH), 7.34-7.63(m, 4H,ArH, ArNH), 2.20-2.34(br-t, J=6.4Hz, 2H, --CH₂ --), 1.53-1.90(m, 8H,--CH₂ --), 1.20-1.47 (m, 16H, --CH₂ --), 0.84 (t, J=5.1Hz, --CH₃)

REFERENCE EXAMPLE 6 Synthesis of5-chloro-2,2,4,6-tetramethyl-7-nitro-2,3-dihydrobenzofuran

A 50 g amount of 4-chloro-3,5-xylenol was dissolved in 50 ml of drymethanol. A 73.9 g amount of sodium methoxide (28% methanol solution)and 43.4 g of 3-chloro-2-methyl-1-propene was added thereto, and themixture was heated under reflux with stirring for 28 hrs. The reactionmixture was cooled, the solvent was removed by evaporation, 300 ml ofwater was added to the residue, and the mixture was extracted with ethylacetate (150 ml×three times). The organic layer was washed with a 5Naqueous sodium hydroxide solution (70 ml×two times), water and brine anddried over anhydrous magnesium sulfate, and the solvent was removed byevaporation to provide 66.6 g of a pale yellow oleaginous substance. A25 g amount of anhydrous magnesium chloride was added to the oleaginoussubstance, and the mixture was heated at 200° C. with stirring for 24hrs. The reaction mixture was cooled, 500 ml of water was added thereto,and the mixture was extracted with methylene chloride (250 ml×threetimes). The organic layer was washed with a 5N aqueous sodium hydroxidesolution (100 ml), a 1N aqueous hydrochloric acid solution (100 ml) andbrine in that order and dried over anhydrous magnesium sulfate, and thesolvent was removed by evaporation to provide 64.8 g of a pale greenoleaginous substance.

Then, this product was dissolved in 300 ml of acetic anhydride, and29.09 g of nitric acid (70%) was slowly added thereto under ice cooling.The stirring was continued for additional one hour to precipitatecrystal. The reaction was allowed to proceed at room temperature foradditional 2 hr, the reaction mixture was poured into 500 ml of water,and the mixture was extracted with ethyl acetate (300 ml×3 times). Theorganic layer was washed with an aqueous sodium hydroxide solution (2N,200 ml×2 times), water and saturated saline in that order and dried overanhydrous magnesium sulfate, and the solvent was removed by evaporationto provide pale brown crystals. This crystal was dissolved in 350 ml ofhexane with heating, insolubles were removed by filtration, and thefiltrate was subjected to recrystallization. The resultant crystals werefurther recrystallized from ethanol to provide 31.4 g of the intendedcompound (5-chloro-2,2,4,6-tetramethyl-7-nitro-2,3-dihydrobenzofuran) aspale yellow crystals (yield: 38.5%). The melting point (m.p.) was 111°to 112° C.

REFERENCE EXAMPLE 7 Synthesis of 7-amino-2,2,4,6-tetramethyl-2,3-dihydrobenzofuran hydrochloride

A 20.00 g amount of5-chloro-2,2,4,6-tetramethyl-7-nitro-2,3-dihydrobenzofuran was dissolvedin 300 ml of ethyl acetate, 2.0 g of Pd-C (10%) was added thereto, andthe mixture was subjected to hydrogenation at room temperature under ahydrogen gas pressure of one arm with vigorous stirring. After 24 hrsfrom the initiation of the hydrogenation, the consumption of hydrogengas was about 6 liters. A 30 ml amount of triethylamine, 4.0 g of Pd-C(10%) and 100 ml of ethanol were added thereto, and the hydrogenationwas continued for additional 24 hrs. After the completion of thereaction was confirmed by TLC, Pd-C was removed by filtration and thesolvent was removed by evaporation. A 300 ml amount of water was addedto the resultant solid, and the mixture was extracted with ethyl acetate(150 ml×3 times). The organic layer was washed with an aqueous sodiumhydroxide solution (1N, 100 ml×2 times), water (100 ml) and brine (50ml) in that order and dried over anhydrous magnesium sulfate, thesolvent was removed by evaporation, and the residue was sufficientlydried to provide pale brown crystals. These crystals were dissolved in100 ml of ethanol, about 40 ml of an ethanol solution (7N) ofhydrochloric acid was added thereto, and the solvent was removed bydistillation to provide a crude hydrochloride. The crude hydrochloridewas dissolved in 50 ml of methylene chloride with heating, insolubleswere removed by filtration, and 400 ml of ethyl acetate was added to thefiltrate with heating to effect recrystallization. The resultant crystalwas collected by filtration, washed with a small amount of ethyl acetateand then dried to provide 14.47 g of the intended product, i.e.,7-amino-2,2,4,6-tetramethyl-2,3-dihydrobenzofuran hydrochloride. Theyield was 72%.

Colorless plate crystal m.p.: 176°-178° C. (sublimable) ¹ H NMR (CDCl₃)δ (ppm): 6.45 (s, 1H), 3.47(s, 3H), 2.91(s, 2H), 2.57(s, 3H), 2.13(s,3H), 1.49(s, 6H)

REFERENCE EXAMPLE 8 Synthesis of2,2,6-trimethyl-2,3-dihydrobenzofuran-7-yl isocyanate

A 400 mg amount of 7-amino -2,2,6-trimethyl-2,3-dihydrobenzofuran wasdissolved in 10 ml of carbon tetrachloride, and 246 mg of triphosgenewas added thereto. The reaction solution was heated to 80° C., and 229mg of triethylamine was slowly added thereto with stirring. Further, themixture was heated under reflux for 1.5 hr. The reaction mixture wasfiltered through Celite to remove insolubles. The solvent was removed byevaporation to provide 461 mg of the title compound.

¹ H NMR(CDCl₃) δ (ppm): 6.82 (d, 1H, J=7.5Hz), 6.59 (d, 1H, J=7.5Hz),3.02 (s, 2H), 2.2-4(s, 3H), 1.50(s, 6H)

EXAMPLE 3 Synthesis of1-[(1-phenylcyclopentyl)methyl-3-(2,2,6-trimethyl-2,3-dihydrobenzofuran-7-yl)urea(309) ##STR212##

A 60 mg amount of (1-phenycyclopentyl)methylamine was added to asolution of 70 mg of 2,2,6-trimethyl-2,3-dihydrobenzofuran-7-ylisocyanate in 2 ml of ethyl acetate, and the mixture was stirred at roomtemperature for 15 hrs. The solvent was removed by evaporation underreduced pressure, and the residue was subjected to recrystallization toprovide 65 mg of the intended title compound.

Property values ¹ H NMR (CDCl₃) δ (ppm): 7.0-7.2(m, 5H), 6.95(d, 1H,J=9Hz), 6.65(d, 1H, J=9Hz), 5.4 (br-s, 1H), 4.3 (br-s, 1H), 3.2-3.4 (m,2H), 2.93(s, 3H), 2.14(s, 3H), 1.5-2.1(m, 8H), 1.52 (s, 6H) m.p.:186°-186.5° C.

EXAMPLE 4 Synthesis ofN-(2,2,6-trimethyl-2,3-dihydrobenzofuran-7-yl)hexadecaneamide (429)##STR213##

A 171 mg amount of hexadecanecarboxylic acid chloride was added to asolution of 100 mg of 7-amino-2,2,6-trimethyl-2,3-dihydrobenzofuran and63 mg of triethylamine in 2 ml of dichloromethane, and the mixture wasstirred at room temperature for one hour. A 10 ml amount of a saturatedsodium hydrogencarbonate solution was added thereto, and the mixture wasextracted twice with 20 ml of ethyl acetate.

The extract was dried over anhydrous magnesium sulfate, filtered,concentrated and purified by column chromatography (hexane/ethylacetate) to provide 193 mg of the intended title compound.

¹ H NMR (CDCl₃) δ (ppm): 6.95(d, 1H, J=9Hz), 6.68(d, 1H, J=9Hz),6.7(br-s, 1H), 2.99(s, 2H), 2.4(br-s, 2H), 2.19(s, 3H), 1.66(br-t, 2H,J=9Hz), 1.44(s, 6H), 1.05-1.5(m, 24H), 0.89(br-t, 3H, J=5Hz) m.p.76°-76.5° C.

EXAMPLE 5 Synthesis ofN-(2,2,4,6-tetramethyl-2,3-dihydrobenzofuran-7-yl)-2,2-dimethyldodecaneamide(434) ##STR214##

A 233 mg amount of 7-amino -2,2,4,6-tetramethyl-2,3-dihydrobenzofuranhydrochloride was dissolved in 3 ml of dichloromethane, and 0.28 ml oftriethylamine was added thereto. 248 mg of2,2-dimethyldodecanecarboxylic acid chloride was slowly added thereto,and the mixture was stirred at room temperature for 15 hrs. A 15 mlamount of 2N hydrochloric acid was added thereto, the resultantdichloromethane layer was separated, and the water layer was furtherextracted with ethyl acetate (25 ml×three times). The organic layerswere combined with each other and washed with water and brine in thatorder. Anhydrous magnesium sulfate was added thereto to dry the washedorganic layer. The solvent was removed by evaporation to provide 413 mgof the title compound. This product was purified by silica gelchromatography (hexane/ethyl acetate) to provide 370 mg of a colorlesscrystal. The yield was 92%.

¹ H NMR (CDCl₃) δ (ppm): 6.79(bs, 1H), 6.50(s, 1H), 2.89(s, 2H), 2.14(s,3H), 2.13(s, 3H), 1.5-1.6(m, 2H), 1.43(s, 6H), 1.2-1.5(m, 22H), 0.88(t,3H, J=6.6Hz) m.p.: 57°-58.5° C.

EXAMPLE 6 Synthesis ofN-(2,2,4,6-tetramethyl-5-nitro-2,3-dihydrobenzofuran-7-yl)-2,2-dimethyldodecaneamide(485) ##STR215##

A 64 mg amount ofN-(2,2,4,6-tetramethyl-2,3-dihydrobenzofuran-7-yl)-2,2-dimethyldodecaneamide(434) was dissolved in 0.5 ml of acetic anhydride, and 24 mg of nitricacid was slowly added to the solution while cooling the solution to 0°C. The mixture, as such, was allowed to react at 0° C. for one hour withstirring. The reaction solution was diluted with 5 ml of ice-cold water,10 ml of a saturated aqueous sodium hydrogencarbonate solution was addedthereto to effect neutralization, and the mixture was extracted withethyl acetate (20 ml×twice). The organic layer was washed with water andbrine in that order and dried over anhydrous magnesium sulfate. Thesolvent was removed by evaporation, and 72 mg of the resultant crudeproduct was purified by silica gel column chromatography (hexane/ethylacetate) to provide 56 mg of the intended tittle compound. The yield was78%.

¹ H NMR (CDCl₃) δ (ppm): 6.80(br-s, 1H), 2.97(s, 2H), 2.15(s, 3H),2.11(s, 3H), 1.5-1.6(m, 2H), 1.47(s, 6H), 1.2-1.5(m, 22H), 0.88 (t, 3H,J=6.5Hz) Pale yellow crystal m.p.: 88°-90° C. (recrystallized fromhexane)

EXAMPLE 7 Synthesis ofN-(5-amino-2,2,4,6-tetramethyl-2,3-dihydrobenzofuran-7-yl)-2,2-dimethyldodecaneamide(486) ##STR216##

A 2.0 g amount ofN-(2,2,4,6-tetramethyl-5-nitro-2,3-dihydrobenzofuran-7-yl)-2,2-dimethyldodecaneamide(485) was dissolved in 30 ml of ethanol, 600 mg of Pd-C (10%) was addedthereto, and the mixture was subjected to hydrogenation at roomtemperature with vigorous stirring. After 24 hrs from the initiation ofthe hydrogenation, the reaction was completed. Pd-C was removed byfiltration with Celite, and the solvent was removed by evaporation toprovide 1.75 g of the intended title compound as a solid. The yield was94%.

¹ H NMR (CDCl₃) δ (ppm): 6.86(br-s, 1H), 3.26(br-s, 2H), 2.92(s, 2H),2.15(s, 3H), 2.04(s, 3H), 1.5-1.65(m, 2H), 1.40(s, 6H), 1.2-1.5(m, 22H),0.88(t, 3H, J=6.5Hz) m.p.: 125° C. (recrystallized from hexane anddichloromethane)

EXAMPLE 8 Synthesis of N-(5-dimethylamino-2,2,4,6-tetramethyl-2,3-dihydrobenzofuran-7-yl)-2,2-dimethyldodecaneamide(490) ##STR217##

A 1.75 g amount ofN-(5-amino-2,2,4,6-tetramethyl-2,3-dihydrobenzofuran-7-yl)-2,2-dimethyldodecaneamide(486) was dissolved in 30 ml of ethanol, 4.26 g of a formaldehydesolution (37%) and 600 mg of platinum dioxide were added thereto, andthe mixture was subjected to hydrogenation at room temperature. After 7hrs from the initiation of the hydrogenation, the catalyst was removedby filtration with Celite, and the solvent was removed by evaporation. A50 ml amount of water was added to the residue, and the mixture wasextracted with ethyl acetate (30 ml×three times). The organic layer waswashed with water and brine and dried over anhydrous magnesium sulfate.The solvent was removed by distillation to provide 2.25 g of a lightbrown oleaginous substance. The oleaginous substance was purified bysilica gel column chromatography (hexane/ethyl acetate) to provide 1.33g of the intended title compound. The yield was 71.4%.

¹ H NMR (CDCl₃) δ (ppm): 6.82(br-s, 1H), 2.89(s, 2H), 2.79(s, 6H),2.10(s, 1.2-1.5(m, 22H), 0.88(t, 3H, J=6.6Hz) Colorless crystal m.p.:84.5°-85° C.

EXAMPLE 9 Synthesis ofN-(5-dimethylamino-2,2,4,6-tetramethyl-2,3-dihydrobenzofuran-7-yl)-2,2-dimethyldodecaneamidehydrochloride (490 hydrochloride)

A 452 mg amount of free base of the compound (490) prepared in Example 8was dissolved in 3 ml of ethanol, and 1 ml of ethanol saturated withhydrochloric acid was added thereto to convert the compound to ahydrochloride. The solvent was removed by evaporation, and the resultantcrystal was recrystallized from ethyl acetate to provide 313 mg of theintended title compound.

¹ H NMR(CDCl₃) δ (ppm): 6.85(br-s, 1H), 3.4(br-s, 6H), 2.97(s, 2H),2.65(br-s, 3H), 2.42(br-s, 3H), 1.2-1.65(m, 30H), 0.88(t, 3H, J=6.5Hz)Colorless crystal m.p.: 107°-110° C.

EXAMPLE 10 Synthesis ofN-(2,2,4,6-tetramethyl-2,3-dihydrobenzofuran-7-yl)-[2,2-dimethyl-7-(4-nitrophenyloxy)]heptaneamide(462) ##STR218##

A 410 mg amount ofN-(2,2,4,6-tetramethyl-2,3-dihydrobenzofuran-7-yl)-(2,2-dimethyl-7-bromo)heptaneamideprepared according to a method described in Example 5 was dissolved in10 ml of acetonitrile together with 139 mg of p-nitrophenol and mg ofpotassium carbonate, and the resultant solution 138 was heated underreflux for 2.5 hr. The solvent was removed by evaporation, 30 ml of a 5Naqueous sodium hydroxide solution was added to the residue, and themixture was extracted with 100 ml of ethyl acetate. The organic layerwas washed with 5N sodium hydroxide, 1N hydrochloric acid, water andbrine in that order and then dried over anhydrous magnesium sulfate. Thesolvent was removed by evaporation to provide 484 mg of an oleaginoussubstance which was then purified by silica gel column chromatography toprovide 354 mg of the intended title compound.

Pale yellow crystal ¹ H NMR(CDCl₃) δ (ppm): 8.17(d, 2H, J=9.3Hz),6.91(d, 2H, J=9.3Hz), 6.8(br-s, 1H), 6.49(br-s, 1H), 4.04(t, 2H,J=6.5Hz), 2.88(s, 2H), 2.13(s, 6H), 1.25-2.0(m, 20H) m.p.: 93°-94° C.

EXAMPLE 11 Synthesis ofN-(2,2,4,6-tetramethyl-2,3-dihydrobenzofuran-7-yl)-2,2-dimethyl-8-(N-isopropyl)aminooctaneamide(469) ##STR219##

A 203 mg amount ofN-(2,2,4,6-tetramethyl-2,3-dihydrobenzofuran-7-yl)-2,2-dimethyl-8-bromooctaneamideand 150 mg of potassium carbonate were added to 7 ml of isopropylamine,and the mixture was allowed to react under reflux for 14 hrs.

After the completion of the reaction, excess isopropylamine was removedby distillation under reduced pressure. Ethyl acetate and 2Nhydrochloric acid were added to the residue, followed by separation. A2N aqueous sodium hydroxide solution was added the water layer to renderthe solution basic, and the liberated compound was extracted with ethylacetate.

The organic solvent was removed by distillation under reduced pressureto provide 54 mg of the title compound.

¹ H NMR (CDCl₃) δ (ppm): 6.79(br, 1H), 6.48(s, 1H), 3.19(br, 1H),2.88(s, 2H), 2.61(t, J=7.0Hz 2H), 2.13(s, 6H), 1.42(s, 6H), 1.27(s, 6H),1.28-1.65(m, 10H), 1.10(d, J=6.2Hz 6H)

Preparation of hydrochloride

Hydrochloric acid/ether was added to 54 mg of the title compound until aprecipitate did not occur any longer. The precipitate was collected byfiltration and subjected to recrystallization from ethyl acetate toprovide 30 mg of a hydrochloride of the title compound.

Property value m.p.: 129°-130° C.

EXAMPLES 12 TO 86

Compounds of the present invention were synthesized in the same manneras that of Examples 1 to 11, except that respective correspondingstarting compounds and reactants were used. Property values thusproduced are given in the following Table 1. Compound Nos. described inTable 1 represent respective numbers given to the compounds listed aboveas favorable specific examples.

                                      TABLE 1    __________________________________________________________________________    Compound   .sup.1 H NMR Data          Yield m.p.  Synthetic    No.        (CDCl.sub.3) δ (ppm) (%)   (°C.)                                                      method    __________________________________________________________________________    Example         106   8.16-8.28(m, 2H), 7.30-7.74(m, 6H), 6.55(s, 1H),                                          68    130-132                                                      According    12         4.86(br-s, 1H), 3.31(m, 2H), 1.16-1.73(m, 20H),                                                      to87               (t, 3H, J=5.3Hz)                       Example 1    Example         107   8.18-8.29(m, 2H), 7.49-7.56(m, 4H), 6.88-7.02(m,                                          55)   248.9-249.3                                                      According    13         5.86(br-s, 1H), 4.03(br-t, 1H, J=5.7Hz), 3.33(d,                                                249.3 to               J=5.7Hz), 2.34(s, 3H), 2.15(s, 3H), 1.55-1.94(m,                                                      Example 1    Example         206   9.13(br, 1H), 8.76(br-d, 1H, J=4.0Hz), 8.52(ddd,                                          93,   139   According    14         J=8.1Hz, 2.0Hz, 2.0Hz), 8.11(br-d, 1H, J=7.7Hz)                                                      to71               (br-s, 1H), 7.23-7.58(m, 3H), 2.44(br-t, 2H,                                                      Example 2               Hz), 1.26-1.60(m, 26H), 0.88(br-t, 3H J=5.1Hz)    Example         208   7.82(br, 1H), 7.44(dd, 1H, J=8.1Hz, 1.5Hz), 7.33(dd,                                           5    --    According    15         1H, J=8.1Hz, 1.5Hz), 6.80(dd, 1H, J=8.1Hz, 8.1Hz),                                                      to               2.44(t, 2H, J=7.9Hz), 1.26-1.80(m, 26H), 0.88(br,                                                      Example 2    Example         209   6.94-7.94(m, 4H), 2.02-2.16(m, 5H), 1.55-1.82(m,                                          72),  48-51 According    16         1.25-1.37(m, 16H), 0.87(br-t, 3H, J=5.5Hz)                                                      to                                                      Example 2    Example         210   8.19-8.28(m, 3H), 7.23-7.58(m, 5H), 2.51(t, 2H,                                          54    137-139                                                      According    17         7.0Hz), 1.17-1.82(m, 26H), 0.88(br, 3H)                                                      to                                                      Example 2    Example         211   8.02-8.28(m, 3H), 7.31-7.72(m, 6H), 2.28(br-t,                                          51,    99   According    18         J=6.8Hz), 1.66-1.85(m, 8H), 1.16-1.49(m, 18H),                                                      to84               (br-t, 3H, J=5.5HZ)                    Example 2    Example         212   8.07-8.18(m, 2H), 7.22-7.45(m, 5H), 7.25(d, 2H,                                          62    Oily  According    19         8.8Hz), 6.77(d, 2H, J=8.8Hz), 3.97(br, 2H), 2.37(s,                                                Substance                                                      to               3H), 2.18(s, 3H), 1.53-1.86(m, 6H), 1.41(s, 6B),                                                      Example 2               (s, 9H)    Example         213   8.09-8.20(m, 2H), 7.45-7.51(m, 4H), 7.17(s, 1H),                                          18    Oily  According    20         2.38(s, 3H), 2.21(s, 3H), 1.14-1.87(m, 26H),                                                Substance                                                      to               (br, 3H)                               Example 2    Example         306   7.21(s, 2H), 6.57(s, 2H), 5.85(br-s, 2H), 2.97(s,                                          50    228-229                                                      According    21         4H), 2.16(s, 6H), 1.45(s, 12H)         to                                                      Example 3    Example         307   6.92(d, 2H, J=7.5Hz), 6.67(d, 2H, J=7.5Hz), 5.9(br-                                          43    151-159                                                      According    22         s, 2H), 2.99(s, 4H), 2.30(s, 6H), 1.47(s, 12H)                                                      to                                                      Example 3    Example         308   6.94(d, 1H, J=8Hz), 6.69(d, 1H, J=8Hz), 5.65(br-s,                                          55    67-68 According    23         1H), 4.7(br-s, 1H), 3.1-3.35(m, 2H), 3.01(s,                                                      to),               2.25(s, 3H), 1.46(s, 6H), 1.1-1.6(m, 20H), 0.88(br-                                                      Example 3               t, 3H, J=7Hz)    Example         310   6.99(s, 1H), 6.60(s, 1H), 5.64(s, 1H), 4.4(br-s,                                          76),  85-86 According    24         3.2(m, 2H), 2.97(s, 2H), 2.21(s, 3H), 1.1-1.7(m,                                                      to               26H), 0.88(br-t, 3H, J=7Hz)            Example 3    Example         311   7.0-7.3(m, 5H), 6.78(s, 1H), 6.53(s, 1H), 5.55(br-s,                                          83    192-193                                                      According    25         1H), 4.1(br-s, 1H), 3.2-3.4(m, 2H), 2.89(s, 2H),                                                      to               2.10(s, 3H), 1.5-2.1(m, 8H), 1.46(s, 6H)                                                      Example 3    Example         405   7.86(br-d, 2H, J=6.5Hz), 6.94(br-d, 2H, J=6.5Hz)                                          59    85-88 According    26         7.25(br-s, 1H), 6.56(s, 1H), 4.00(m, 2H), 2.91(s,                                                      to               2H), 2.22(s, 3H), 2.16(s, 3H), 1.8(m, 2H), 1.3-1.6                                                      Example 5               (m, 18H), 0.89(t, 3H, J=6.7Hz)    Example         406   7.85(d, 2H, J=8Hz), 7.22(br-s, 1H), 6.93(d, 2H,                                          998   97-98 According    27         Hz), 6.55(s, 1H), 4.00(t, 2H, J=6.5Hz), 2.90(s,                                                      to),               2.21(s, 3H), 2.16(s, 3H), 1.1-1.9(m, 22H), 0.88(t,                                                      Example 5               3H, J=7Hz)    Example         407   7.85(d, 2H, J=7Hz), 7.24(br-s; 1H), 6.93(d, 2H,                                          997   57-60 According    28         Hz), 6.55(s, 1H), 4.00(t, 2H, J=6.5Hz), 2.90(s,                                                      to),               2.22(s, 3H), 2.16(s, 3H), 1.2-1.9(m, 24H), 0.88(t,                                                      Example 5               3H, J=7Hz)    Example         409   7.85(br-d, 2H, J=8.3Hz), 7.26(s, 1H), 6.93(br-d,                                          98,   69-71 According    29         J=8.3Hz), 6.56(s, 1H), 4.01(t, 2H, J=7.4Hz),                                                      to4(t,               2H, J=6.5Hz), 3.37(t, 2H, J=6.8Hz), 2.91(s, 2H),                                                      Example 5               2.22(s, 3H), 2.16(s, 3H), 1.82(m, 2H), 1.4-1.7(m, 16H)    Example         410   7.85(br-d, 2H, J=8.8Hz), 7.20(br-s, 1H), 6.94(br-d,                                          54    91-97 According    30         2H, J=8.8Hz), 6.56(s, 1H), 4.01(t, 2H, J=6.4Hz),                                                      to               3.41(t, 2H, J=6.4Hz), 3.17(d, 2H, J=6.8Hz), 2.92(s,                                                      Example 5               2H), 2.22(s, 3H), 2.16(s, 3H), 1.83(m, 3H), 1.4-1.7               (m, 14H), 0.91(d, 6H, J=6.8Hz)    Example         411   7.86(br-d, 2H, J=8Hz), 7.22(d, 2H, J=9Hz), 7.2(br-s,                                          86    135-136                                                      According    31         1H), 6.93(br-d, 2H, J=8Hz), 6.81(d, 2H, J=9Hz),                                                      to56               (s, 1H), 4.03(t, 2H, J=6.5Hz), 3.94(t, 2H, J=6.5Hz),                                                      Example 5               2.92(s, 2H), 2.21(s, 3H), 2.16(s, 3H), 1.83(m, 4H),               1.4-1.7(m, 14H)    Example         412   6.84(s, 6H), 6.58(s, 2H), 6.57(s, 1H), 3.94(t,                                          47,   Oily  According    32         J=6.6Hz), 2.93(s, 2H), 2.45(s, 6H), 2.34(s, 3H),                                                Substance                                                      to               2.16(s, 3H), 1.77(m, 2H), 1.2-1.6(m, 20H), 0.88(t,                                                      Example 5               3H, J=7.1Hz)    Example         413   7.76(br-d, 2H, J=8.7Hz), 7.19(br, 1H), 6.60(d,                                          24,   --    According    33         J=8.7Hz), 6.54(s, 1H), 3.16(t, 2H, J=7.2Hz),                                                      to91               (s, 2H), 2.21(s, 3H), 2.16(s, 3H), 1.43(s, 6H),                                                      Example 5               1.47(m, 16H), 0.89(t, 3H, J=7.2Hz)    Example         427   8.0(br-s, 1H), 6.75-7.3(m, 3H), 3.04(s, 2H),                                          902-2.5                                                90-92 According    34         (m, 2H), 1.15-1.9(m, 26H), 1.48(s, 6H), 0.88                                                      tor-t,               3H, J=7Hz)                             Example 4    Example         428   8.0-8.15(m, 1H), 7.4(br, 1H), 6.7-6.9(m, 2H),                                          9104  Oily  According    35         (s, 2H), 2.0-2.3(m, 2H), 1.0-1.9(m, 30H), 0.87                                                Substance                                                      to               3H, J=7Hz)                             Example 4    Example         430   6.89(d, 1H, J=8Hz), 6.80(br-s, 1H), 6.65(d, 1H,                                          98     97-107                                                      According    36         8Hz), 2.97(s, 2H), 2.18(s, 3H), 2.0-2.35(m, 2H),                                                      to               1.05-1.8(m, 30H), 0.87(br-t, 3H, J=7Hz)                                                      Example 4    Example         431   7.27(d, 2H, J=9.0Hz), 6.55-6.98(m, 5H), 3.95(t,                                          95    101-103                                                      According    37         J=6.3Hz), 2.97(s, 2H), 2.17(s, 3H), 1.45-1.9(m,                                                      to),               1.41(s, 6H), 1.1-1.4(m, 15H)           Example 4    Example         432   6.78(br-s, 1H), 6.49(s, 1H), 3.40(t, 2H, J=6.9Hz),                                          73    80-81 According    38         2.88(s, 2H), 2.13(s, 6H), 1.1-2.0(m, 10H), 1.43(s,                                                      to               6H), 1.29(s, 6H)                       Example 5    Example         433   6.77(br, 1H), 6.49(s, 1H), 2.88(s, 2H), 2.13(s,                                          93),  81-82 According    39         1.0-1.7(m, 26H), 0.88(br-t, 3H, J=6Hz) to                                                      Example 5    Example         435   6.78(br-s, 1H), 6.49(s, 1H), 2.89(s, 2H), 2.13(s,                                          68    36-38 According    40         6H), 1.0-1.7(m, 34H), 0.85(br-t, 3H, J=7Hz)                                                      to                                                      Example 5    Example         437   7.19(br, 5H), 6.77(br, 1H), 6.49(s, 1H), 2.89(s,                                          29)     73-73.8                                                      According    41         2.62(t, 2H, J=7.3Hz), 2.12(s, 6H), 1.43(s, 6H),                                                      to28               (s, 6H), 1.28-1.72(m, 6H)              Example 5    Example         438   7.1-7.3(m, 5H), 6.78(br-s, 1H), 6.49(s, 1H),                                          7888  69-71 According    42         (s, 2H), 2.60(t, 2H, J=8Hz), 2.13(s, 6H), 1.2-1.9                                                      to               (m, 8H); 1.41(s, 6H), 1.27(s, 6H)      Example 5    Example         439   7.1-7.4(m, 5H), 6.75(br-s, 1H), 6.48(s, 1H),                                          8587  51-52 According    43         (s, 2H), 2.59(t, 2H, J=6.5Hz), 2.13(s, 6H), 1.0-1.8                                                      to               (m, 10H), 1.40(s, 6H), 1.27(s, 6H)     Example 5    Example         440   7.09(d, 2H, J=7.9Hz), 7.06(d, 2H, J=7.9Hz), 6.76                                          96    88-91 According    44         (br-s, 1H), 6.49(s, 1H), 2.87(s, 2H), 2.59(t, 2H,                                                      to               7.5Hz), 2.54(t, 2H, J=7.5Hz), 2.13(s, 6H), 1.5-1.8                                                      Example 5               (m, 6H), 1.38(s, 6H), 1.28(s, 6H), 0.93(t, 3H, J=               7.2Hz)    Example         441   6.9-7.2(m, 4H), 6.75(br-s, 1H), 6.49(s, 1H),                                          8287   98-100                                                      According    45         (s, 2H), 2.2-2.7(m, 4H), 2.13(s, 6H), 1.4-1.95(m,                                                      to               5H), 1.38(s, 6H), 1.28(s, 6H), 0.89(d, 6H, J=6.5Hz)                                                      Example 5    Example         442   7.08(d, 2H, J=8.6Hz), 6.80(d, 2H, J=8.6Hz), 6.77                                          85    Oily  According    46         (br, 1H), 6.50(s, 1H), 3.91(t, 2H, J=6.6Hz),                                                Substance                                                      to               (s, 2H), 2.57(t, 2H, J=6.6Hz), 2.13(s, 6H), 1.2-1.8                                                      Example 5               (m, 24H), 0.90(t, 3H, J=6.9Hz)    Example         443   6.8(br-s, 1H), 6.49(s, 1H), 3.25-3.55(m, 4H),                                          8189  Oily  According    47         (s, 2H), 2.13(s, 6H), 1.0-1.8(m, 23H), 0.87(d,                                                Substance                                                      to               J=6, 2Hz)                              Example 5    Example         444   6.77(br-s, 1H), 6.49(s, 1H), 3.37(t, 4H, J=6.4Hz),                                          61    Oily  According    48         2.88(s, 2H), 2.13(s, 6H), 1.0-1.8(m, 37H), 0.88(d,                                                Substance                                                      to               6H, J=6.1Hz)                           Example 5    Example         445   6.8(br-s, 1H), 6.49(s, 1H), 3.38(t, 2H, J=6.5Hz),                                          66    45-47 According    49         3.15(d, 2H, J=6.5Hz), 2.88(s, 2H), 2.13(s, 6H),                                                      to               1.1-1.9(m, 23H), 0.89(d, 6H, J=6.5Hz)  Example 5    Example         446   6.77(br-s, 1H), 6.49(s, 1H), 3.38(t, 2H, J=6.2Hz),                                          42    Oily  According    50         3.03(s, 2H), 2.89(s, 2H), 2.13(s, 6H), 1.1-1.75                                                Substance                                                      to               (m, 22H), 0.89(s, 9H)                  Example 5    Example         447   6.78(br, 1H), 6.49(s, 1H), 3.39(t, 2H, J=6.3Hz),                                          46    Oily  According    51         3.15(d, 2H, J=6.8Hz), 2.88(s, 2H), 2.13(s, 6H),                                                Substance                                                      to               2.1(m, 21H), 0.88(d, 6H, J=6.6Hz)      Example 5    Example         448   6.8(br, 1H), 6.49(s, 1H), 3.3-3.6(m, 2H), 2.89(s,                                          30    Oily  According    52         2H), 2.13(s, 6H), 1.1-1.95(m, 33H)                                                Substance                                                      to                                                      Example 5    Example         449   7.2-7.4(m, 5H), 6.80(br-s, 1H), 6.49(s, 1H),                                          5448  78-79 According    53         (s, 2H), 3.47(t, 2H, J=6.5Hz), 2.88(s, 2H), 2.13(s,                                                      to               6H), 1.2-1.8(m, 6H), 1.41(s, 6H), 1.28(s, 6H)                                                      Example 5    Example         450   7.23(s, 5H), 6.8(br-s, 1H), 6.49(s, 1H), 3.61(t,                                          31,   Oily  According    54         J=7Hz), 3.42(t, 2H, J=7Hz), 2.7-3.0(m, 4H), 2.13(s,                                                Substance                                                      to               6H), 1.2-1.8(m, 20H)                   Example 5    Example         451   6.78(br, 1H), 6.49(s, 1H), 3.3-3.8(m, 3H), 3.55(s,                                          49    Oily  According    55         4H), 2.88(s, 2H), 2.13(s, 6H), 1.0-1.8(m, 26H)                                                Substance                                                      to                                                      Example 5    Example         452   6.8(br, 1H), 6.49(s, 1H), 3.39(t, 2H, J=6Hz),                                          --31  Oily  According    56         (s, 3H), 2.89(s, 2H), 2.13(s, 6H), 1.2-1.9(m,                                                Substance                                                      to                                                      Example 5    Example         453   7.20(d, 2H, J=9Hz), 6.85(br-s, 1H), 6.78(d, 2H,                                          75    116.5-117                                                      According    57         9Hz), 6.50(s, 1H), 3.93(t, 2H, J=6Hz), 2.89(s,                                                      to),               2.14(s, 6H), 1.5-1.9(m, 4H), 1.41(s, 6H), 1.33(s,                                                      Example 5               6H)    Example         454   7.27(d, 2H, J=9Hz), 6.80(d, 2H, J=9Hz), 6.49(s,                                          85    110-111                                                      According    58         1H), 3.94(t, 2H, J=6Hz), 2.88(s, 2H), 2.13(s,                                                      to),               1.4-1.9(m, 6H), 1.41(s, 6H), 1.29(s, 15H)                                                      Example 5    Example         455   7.20(d, 2H, J=9Hz), 6.85(br-s, 1H), 6.79(d, 2H,                                          87    91-92 According    59         9Hz), 6.50(s, 1H), 3.92(t, 2H, J=6Hz), 2.88(s,                                                      to),               2.16(s, 3H), 2.13(s, 3H), 1.1-1.9(m, 6H), 1.41(s,                                                      Example 5               6H), 1.31(s, 6H)    Example         456   7.1-7.3(m, 2H), 6.7-7.0(m, 4H), 6.49(s, 1H),                                          7195, 108   According    60         (t, 2H, J=6Hz), 2.88(s, 2H), 2.13(s, 6H), 1.3-1.95                                                      to               (m, 8H), 1.42(s, 6H), 1.29(s, 6H)      Example 5    Example         457   7.20(d, 2H, J=9Hz), 6.79(d, 2H, J=9Hz), 6.7(br-s,                                          83    90-91 According    61         1H), 6.49(s, 1H), 3.91(t, 2H, J=6Hz), 2.88(s,                                                      to),               2.13(s, 6H), 1.2-1.95(m, 8H), 1.42(s, 6H), 1.29                                                      Example 5               (s, 6H)    Example         458   7.06(d, 2H, J=8.5Hz), 6.76(d, 2H, J=8.5Hz), 6.8(br-s,                                          87    102-104                                                      According    62         1H), 6.49(s, 1H), 3.92(t, 2H, J=6.5Hz), 2.88(s,                                                      to),               2.27(s, 3H), 2.13(s, 6H), 1.2-1.95(m, 8H), 1.42(s,                                                      Example 5               6H), 1.29(s, 6H)    Example         459   7.05-7.4(m, 2H), 6.7-6.9(m, 2H), 6.49(s, 1H),                                          8298  88-89 According    63         (t, 2H, J=6Hz), 2.88(s, 2H), 2.13(s, 6H), 1.2-1.95                                                      to               (m, 8H), 1.42(s, 6H), 1.30(s, 6H)      Example 10    Example         460   6.5-7.05(m, 4H), 6.49(s, 1H), 3.92(t, 2H, J=6Hz),                                          77    100-102                                                      According    64         2.88(s, 2H), 2.24(s, 3H), 2.17(s, 3H), 2.13(s,                                                      to),               1.1-1.95(m, 8H), 1.42(s, 6H), 1.29(s, 6H)                                                      Example 10    Example         461   7.12(d, 2H, J=9Hz), 6.85(br-s, 1H), 6.80(d, 2H,                                          43    118-120                                                      According    65         9Hz), 6.49(s, 1H), 3.92(t, 2H, J=6Hz), 2.89(s,                                                      to),               2.13(s, 6H), 1.0-2.0(m, 27H)           Example 10    Example         463   6.5-6.9(m, 5H), 6.49(s, 1H), 3.87(t, 2H, J=6Hz),                                          91    100-105                                                      According    66         2.88(s, 2H), 2.13(s, 6H), 1.2-2.0(m, 8H), 1.42(s,                                                      to               6H), 1.29(s, 6H)                       Example 7    Example         464   6.7-6.95(m, 5H), 6.49(s, 1H), 3.89(t, 2H, J=6Hz),                                          60      108-108.5                                                      According    67         2.88(s, 2H), 2.85(s, 6H), 2.13(s, 6H), 1.2-1.9(m,                                                      to               8H), 1.42(s, 6H), 1.28(s, 6H)          Example 8    Example         465   7.19(d, 2H, J=6.9Hz), 6.8(br-s, 1H), 6.79(d,                                          85,   79-80 According    68         J=6.9Hz), 6.49(s, 1H), 3.90(t, 2H, J=6.5Hz),                                                      to88               (s, 2H), 2.13(s, 6H), 1.3-1.9(m, 10H), 1.42(s,                                                      Example 5               1.29(s, 6H)    Example         466   7.16(d, 2H, J=8Hz), 6.85(br-s, 1H), 6.77(d, 2H,                                          38    79-80 According    69         J=8Hz), 6.49(s, 1H), 3.91(t, 2H, J=6Hz), 2.88(s,                                                      to               1H), 2.27(s, 3H), 2.13(s, 6H), 1.2-1.9(m, 10H),                                                      Example 5               1.42(s, 6H), 1.28(s, 6H)    Example         467   6.7-7.1(m, 5H), 6.49(s, 1H), 3.89(t, 2H, J=6Hz),                                          55    71-72 According    70         2.88(s, 2H), 2.13(s, 6H), 1.2-1.9(m, 10H), 1.42(s,                                                      to               6H), 1.28(s, 6H)                       Example 10    Example         468   6.6-6.9(m, 5H), 6.49(s, 1H), 3.89(t, 2H, J=6Hz),                                          6488  Oily  According    71         (s, 2H), 2.85(s, 6H), 2.13(s, 6H), 1.2-1.9(m,                                                Substance                                                      to               1.43(s, 6H), 1.28(s, 6H)               Example 8    Example         470   (Free)6.79(br, 1H), 6.48(s, 1H), 3.44(br, 1H),                                          36    146-149                                                      According    72         2.88(s, 2H), 2.60(t, 2H, J=6.8Hz), 2.12(s, 6H),                                          (HCl salt)                                                (HCl salt)                                                      to               (s, 6H), 1.27(s, 6H), 1.27- 1.69(m, 10H), 1.17(s,                                                      Example 11    Example         471   (Free)7.25(br-s, 4H), 6.78(s, 1H), 6.48(s, 1H),                                          10    191-193                                                      According    73         3.73(s, 2H), 2.88(s, 2H), 2.58(t, 2H, J=7.0Hz),                                          (HCl salt)                                                (HCl salt)                                                      to               (s, 6H), 1.42(s, 6H), 1.27(s, 6H), 1.27-1.64(m,                                                      Example 11    Example         472   (Free)7.28(br, 5H), 6.79(br, 1H), 6.48(s, 1H),                                          79    Amorphous                                                      According    74         3.50(s, 2H), 2.87(s, 2H), 2.38(t, 2H, J=6.2Hz),                                          (HCl salt)  to               (s, 3H), 2.12(s, 6H), 1.41(s, 6H), 1.27(s, 6H),                                                      Example 11               1.27-1.65(m-10H)    Example         473   7.27(d, 2H, J=8.8Hz), 7.17(d, 2H, J=8.8Hz), 6.78                                          28    Oily  According    75         (br, 1H), 6.48(s, 1H), 4.41(s, 2H), 4.10(t, 2H,                                                Substance                                                      to               6.6Hz), 2.88(s, 2H), 2.83(s, 3H), 2.13(s, 6H),                                                      Example 11               (s, 6H), 1.28(s, 6H), 1.27-1.72(m, 10H)    Example         474   (Free)6.86(br, 1H), 6.48(s, 1H), 2.88(s, 2H),                                          26    177-180                                                      According    76         2.32-2.56(m, 6H), 2.12(s, 6H), 1.43(s, 6H), 1.27(s,                                          (HCl salt)                                                (HCl salt)                                                      to               6H), 1.27-1.65(m, 16H)                 Example 5    Example         475   (Free)6.80(br, 1H), 6.48(s, 1H), 2.88(s, 2H),                                          28    175-178                                                      According    77         2.47(br, 10H), 2.28(s, 3H), 2.13(s, 6H), 1.43(s,                                          (HCl salt)                                                (HCl salt)                                                      to               6H), 1.27(s, 6H), 1.27-1.60(m, 10H)    Example 5    Example         476   7.28(br, 5H), 6.88(br, 1H), 6.49(s, 1H), 3.47(s,                                          22    100-101                                                      According    78         2H), 2.89(s, 2H), 2.27-2.49(m, 10H), 2.13(s,                                                      to),               1.42(s, 6H), 1.28(s, 6H), 1.28-1.69(m, 6H)                                                      Example 5    Example         477   7.28(br, 5H), 6.76(br, 1H), 6.48(s, 1H), 3.49(s,                                          55    Oily  According    79         2H), 2.87(s, 2H), 2.22-2.46(m, 10H), 2.12(s,                                                Substance                                                      to               1.42(s, 6H), 1.26(s, 6H), 1.26-1.56(m, 10H)                                                      Example 5    Example         478   7.86(br-d, 2H, J=8.5Hz), 7.26(br-s, 1H), 6.94(br-d,                                          81    97    According    80         2H, J=8.5Hz), 6.56(s, 1H), 4.01(t, 2H, J=6.6Hz),                                                      to               2.91(s, 2H), 2.22(s, 3H), 2.16(s, 3H), 1.83(m,                                                      Example 5               1.2-1.6(m, 26H), 0.89(t, 3H, J=7.5Hz)    Example         480   6.6(br-s, 1H), 6.51(s, 1H), 2.90(s, 3H), 2.1-2.5(m,                                          89      84-85.5                                                      According    81         2H), 2.16(s, 6H), 1.5-1.8(m, 2H), 1.45(s, 6H),                                                      to1-               1.5(m, 24H), 0.88(br-t, 3H, J=7Hz)     Example 5    Example         481   6.73(br-s, 1H), 6.49(s, 1H), 2.89(s, 2H), 2.0-2.45                                          73    65-66 According    82         (m, 2H), 2.13(s, 6H), 1.1-1.85(m, 30H), 0.87(br-t,                                                      to               3H, J=7Hz)                             Example 5    Example         482   6.5(br-s, 1H), 2.96(s, 2H), 2.1-2.5(m, 2H), 2.22(s,                                          65    114-115                                                      According    83         6H), 1.55-1.9(m, 2H), 1.50(s, 3H), 1.45(s, 3H),                                                      to               1.05-1.4(m, 24H), 0.87(br-t, 3H, J=7Hz)                                                      Example 4    Example         483   6.78(br, 1H), 2.95(s, 2H), 2.0-2.35(m, 2H), 2.20                                          87    69-70 According    84         (s, 6H, 1.1-1.8(m, 30H), 0.88(br-t, 3H, J=7Hz)                                                      to                                                      Example 4    Example         521   7.36(s, 1H), 6.77(br, 1H), 6.55(s, 1H), 2.97(s,                                          86),  85-87 According    85         2.0-2.5(m, 2H), 2.17(s, 2H), 2.5-2.8(m, 2H),                                                      to45               (s, 6H), 1.05-1.55(m, 24H), 0.88(br-t, 3H, J=7Hz)                                                      Example 4    Example         522   7.42(s, 1H), 6.94(br-s, 1H), 6.54(s, 1H), 2.96(s,                                          70     66   According    86         2H), 2.0-2.5(m, 5H), 1.1-1.9(m, 30H), 0.87(br-t,                                                      to,               J=7Hz)                                 Example    __________________________________________________________________________                                                      4

EXAMPLE 87 Synthesis ofN-(2,2,4,6-tetramethyl-2,3-dihydrobenzofuran-7-yl)-4-(4-chlorobenzyloxy)benzoylamide(408) ##STR220##

A 62 mg amount ofN-(2,2,4,6-tetramethyldihydro-1-benzofuran-7-yl)-4-hydroxybenzoylamidewas dissolved in 2 ml of acetonitrile. A 38 mg amount of 4-chlorobenzylchloride and 41 mg of potassium carbonate were added thereto, and themixture was allowed to react under reflux for 10 hrs.

After the completion of the reaction, potassium carbonate was removed,the residue was concentrated by removing the solvent, and theconcentrate was purified by preparative thin-layer chromatography(hexane:ethyl acetate=4:6) to provide 72 mg of the title compound.

Property values ¹ H NMR (CDCl₃) δ (ppm): 7.89 (br, 2H), 7.37 (s, 4H),7.25 (br, 1H), 7.01 (br-d, J=8.7Hz, 2H), 6.56(s, 1H), 2.92(s, 2H),2.21(s, 3H), 2.16(s, 3H), 1.44(s, 6H) m.p.: 148°-150° C.

EXAMPLE 88 Synthesis ofN-(2,2,4,6-tetramethyl-2,3-dihydrobenzofuran-7-yl)3-(4-decyloxyphenyl)-3-oxpropaneamide(479) ##STR221##

A 1.36 ml amount of a 1.6M n-butyl lithium hexane solution was added byportions to a solution of 304 μl of diisopropylamine in 5 ml of drytetrahydrofuran at -78° C., and the mixture was stirred at thattemperature for 30 min. Subsequently, a solution of 500 mg of4-decyloxyacetophenone in 5 ml of dry tetrahydrofuran was added at 0°C., and the mixture was stirred at that temperature for 15 min and thenat room temperature for one hour.

Separately, 2,2,4,6-tetramethyl-2,3-dihydrobenzofuran-7-yl isocyanatewas prepared from 412 mg of 2,2,4,6-tetramethyl-7-aminodihydro-1-benzofuran according to the reference examples. The above-describedstirred solution was added to a solution of the2,2,4,6-tetramethyl-2,3-dihydrobenzofuran-7-yl isocyanate in 5 ml of drytetrahydrofuran at room temperature.

The mixture was allowed to react for 15 hrs. An aqueous potassiumhydrogensulfate was added to the reaction mixture, and the mixture wasextracted with ethyl acetate.

The extract was concentrated by removing the organic solvent, and theconcentrate was purified by silica gel column chromatography(hexane:ethyl acetate=6:4). The product was further recrystallized fromhexane to provide 440 mg of the title compound.

Property values ¹ H NMR (CDCl₃) δ (ppm): 8.31 (br, 1H), 8.02 (d,J=8.9Hz, 2H), 6.95 (d, J=8.9Hz, 2H), 6.50(s, 1H), 4.09(s, 2H), 4.03(t,J=6.6Hz, 2H), 2.89(s, 2H), 2.13(s, 3H), 2.11(s, 3H), 1.81(tt, J=6.6Hz,J=6.9Hz, 2H), 1.28-1.55(m, 14H), 0.88 (t, J=6.6Hz, 3H) m.p.: 118.5°-119°C.

EXAMPLE 89 Synthesis ofN-(5-dodecaneamide-2,2,4,6-tetramethyl-2,3-dihydrobenzofuran-7-yl)-2,2-dimethyldodecaneamide(535) ##STR222##

A 42 mg amount ofN-(5-amino-2,2,4,6-tetramethyl-2,3-dihydrobenzofuran-7-yl)-2,2-dimethyldodecaneamide(486) was dissolved in 2.0 ml of dichloromethane, and 13 mg oftriethylamine was added thereto. Further, 22 mg of n-dodecanoyl chloridewas added thereto, and the mixture was allowed to react at roomtemperature with stirring for 5 hr. The reaction solution was pouredinto 20 ml of water, and the mixture was extracted with ethyl acetate(10 ml×three times). The organic layer was washed with water and brinein that order and dehydrated over anhydrous magnesium sulfate, and thesolvent was removed by distillation. The resultant crystal was purifiedby silica gel column chromatography to provide 40 mg of the intendedtitle compound. The yield was 67.6%.

¹ H NMR (CDCl₃) δ (ppm): 6.86(br-s, 1H), 6.70(br-s, 1H), 2.92(s, 2H),2.39(t, 2H, J=7.9Hz), 2.02(s, 3H), 2.00(s, 3H), 1.56(br-t, 4H, J=6Hz),1.1-1.5(m, 32H), 0.88(t, 6H, J=7.6Hz)

EXAMPLE 90 Measurement of ACAT enzyme inhibitory activity (measurementof ACAT enzyme inhibitory activity of rabbit intestinal mucosa)

Preparation of a domestic rabbit intestinal mucosa microsome andmeasurement of the ACAT enzyme activity were conducted by slightlymodifying a method established by Salone and Field (see Biochemica etBiophysica, vol. 712, 557 (1982).

The domestic rabbit intestinal mucosa was homogenized by using a 40 mMphosphate buffer having a pH value of 7.4 (buffer A) containing 30 mMEDTA, 50 mM KCl and 0.1M sucrose and centrifuged at 10,000×g and atemperature of 4° C. for 30 min to provide a supernatant. Thesupernatant was further centrifuged at 105,000×g and a temperature of 4°C. for one hour to provide a precipitate. The precipitate wasresuspended in the buffer A to provide a microsome fraction.

A 1 %v/v dimethylsulfoxide solution of each specimen compound in apredetermined concentration was added to the buffer A containing 43 μMserum albumin and 0.5 mg/ml microsome fraction, and the mixture washeated at 37° C. for 5 min.

Then, 43 μM oleoyl CoA containing [1⁻¹⁴ C] oleoyl CoA (3.7 kB) was addedthereto, the mixture was heated at 37° C. for 10 rain, andchloroform/methanol (2/1) containing 10 mg/ml cholesteryl oleate wasadded thereto to terminate the reaction.

0.111 kB of [³ H] cholesteryl oleate and 1N hydrochloric acid were addedthereto, and the mixture was stirred. The cholesteryl oleate extractedinto the chloroform layer was isolated by thin-layer chromatography, andthe radioactivity was measured as the ACAT activity. The results aregiven in Table 2.

                  TABLE 2    ______________________________________    Test Compound                 ACAT Inhibitory Activity, IC.sub.50 (M)    ______________________________________    Compound of Ex. 2          8.3 × 10.sup.-7    Compound of Ex. 3          3.4 × 10.sup.-7    Compound of Ex. 4          2.4 × 10.sup.-8    Compound of Ex. 5          4.2 × 10.sup.-8    Compound of Ex. 6          1.9 × 10.sup.-8    Compound of Ex. 8          2.0 × 10.sup.-8    Compound of Ex. 10         2.3 × 10.sup.-7    Compound of Ex. 13         4.0 × 10.sup.-7    Compound of Ex. 18         5.0 × 10.sup.-7    Compound of Ex. 23         2.2 × 10.sup.-7    Compound of Ex. 27         3.0 × 10.sup.-8    Compound of Ex. 28         9.0 × 10.sup.-8    Compound of Ex. 33         1.1 × 10.sup.-7    Compound of Ex. 34         8.9 × 10.sup.-7    Compound of Ex. 35         5.0 × 10.sup.-7    Compound of Ex. 36         2.4 × 10.sup.-7    Compound of Ex. 37         3.4 × 10.sup.-7    Compound of Ex. 38         1.8 × 10.sup.-7    Compound of Ex. 39         7.2 × 10.sup.-8    Compound of Ex. 40         3.3 × 10.sup.-8    Compound of Ex. 41         2.1 × 10.sup.-7    Compound of Ex. 42         1.2 × 10.sup.-7    Compound of Ex. 43         8.1 × 10.sup.-8    Compound of Ex. 44         6.6 × 10.sup.-8    Compound of Ex. 45         2.8 × 10.sup.-8    Compound of Ex. 46         3.4 × 10.sup.-8    Compound of Ex. 47         1.9 × 10.sup.-7    Compound of Ex. 48         5.7 × 10.sup.-8    Compound of Ex. 49         5.9 × 10.sup.-8    Compound of Ex. 50         4.5 × 10.sup.-8    Compound of Ex. 51         8.2 × 10.sup.-8    Compound of Ex. 52         4.2 × 10.sup.-8    Compound of Ex. 53         4.0 × 10.sup.-7    Compound of Ex. 54         1.0 × 10.sup.-7    Compound of Ex. 55         1.7 ×  10.sup.-7    Compound of Ex. 56         3.3 × 10.sup.-7    Compound of Ex. 57         2.6 × 10.sup.-7    Compound of Ex. 58         1.7 × 10.sup.-7    Compound of Ex. 59         3.3 × 10.sup.-7    Compound of Ex. 60         8.6 × 10.sup.-8    Compound of Ex. 61         1.5 × 10.sup.-7    Compound of Ex. 62         6.4 × 10.sup.-8    Compound of Ex. 63         2.2 × 10.sup.-7    Compound of Ex. 64         9.1 × 10.sup.-7    Compound of Ex. 65         8.6 × 10.sup.-8    Compound of Ex. 66         4.6 × 10.sup.-7    Compound of Ex. 67         1.9 × 10.sup.-7    Compound of Ex. 68         7.6 × 10.sup.-8    Compound of Ex. 69         5.0 × 10.sup.-8    Compound of Ex. 70         1.1 × 10.sup.-7    Compound of Ex. 71         1.3 × 10.sup.-7    Compound of Ex. 73                 (HCl salt)    3.4 × 10.sup.-7    Compound of Ex. 74                 (HCl salt)    3.3 ×  10.sup.-7    Compound of Ex. 75         1.2 × 10.sup.-7    Compound of Ex. 78         3.3 × 10.sup.-7    Compound of Ex. 79         3.5 × 10.sup.-7    Compound of Ex. 80         4.0 × 10.sup.-8    Compound of Ex. 81         2.6 × 10.sup.-7    Compound of Ex. 82         1.7 × 10.sup.-7    compound of Ex. 83         7.2 × 10.sup.-8    Compound of Ex. 84         2.9 × 10.sup.-7    Compound of Ex. 88         1.1 × 10.sup.-7    Compound of Ex. 9          1.4 × 10.sup.-7    in Japanese Unexam-    ined Patent Publi-    cation (Kokai) No.    63-253060    ______________________________________

All the test compounds had a LD₅₀ value of 2 g/kg or more (mouse).

EXAMPLE 91 Measurement of percentage change of serum cholesterol

Male Wistar rats having a weight of 200 g were preliminarily bred for 7days while they freely ingested a normal feed (CE-2 manufactured by CLEAJapan Inc.).

Thereafter, they were bred for 3 days while they freely ingested a feedenriched with cholesterol and fat (2% cholesterol, 1% cholic acid, 20%casein, 45% fine granulated sugar, 12% coconut oil, 4% KC flock, 1%mixed vitamin, 7% mixed mineral and 8% dried fish powder; a product ofCLEA Japan Inc.). During the cholesterol loading period, the testcompound of the present invention was orally administered to the abovetest animals at a dose of 0.1 to 10 mg per kg of the weight once a dayfor three days. On the other hand, the excipient alone was administeredto the control animals.

After 8 hrs from the last administration, the test animals were fasted.16 hr after the initiation of the fasting, these test animals wereslaughtered. The serum cholesterol level was measured for each animal.

The results were compared with those of the control and are given aspercentage serum cholesterol (%) in Table 3.

    Percentage change of serum cholesterol (%)={(A-B)/B}×100

wherein A represents the total cholesterol level of serum in the groupof rats to which the test compound was administered; and B representsthe total cholesterol level of serum in the control group of rats.

                  TABLE 3    ______________________________________                 Dose in Oral Percentage Change                 Administration                              of Serum    Test Compound                 (mg/kg)      Cholesterol (%)    ______________________________________    Compound of Ex. 5                 1            -61    Compound of Ex. 8                 1            -71    Compound of Ex. 20                 10           -46    Compound of Ex. 29                 1            -23    Compound of Ex. 36                 10           -52    Compound of Ex. 42                 1            -44    Compound of Ex. 45                 1            -58    Compound of Ex. 49                 1            -50    Compound of Ex. 50                 10           -54    Compound of Ex. 53                 10           -50    Compound of Ex. 58                 10           -27    Compound of Ex. 59                 1            -43    Compound of Ex. 61                 1            -64    Compound of Ex. 62                 1            -18    Compound of Ex. 68                 1            -75    Compound of Ex. 71                 1            -49    Compound of Ex. 78                 10           -43    Compound of Ex. 94                 3            -55    ______________________________________

EXAMPLE 92 Preparation of Tablet

A tablet containing 30 mg of the compound of Example 5 was preparedaccording to the following formulation.

    ______________________________________    Compound Ex. 5    30 mg    Lactose           87 mg    Starch            30 mg    Magnesium stearate                       3 mg    ______________________________________

Utilization in Industry

The present invention provides a pharmaceutical composition for use asan ACAT inhibitor and treating hyperlipidemia and atherosclerosis, whichpharmaceutical composition contains a benzoxazole compound and a2,3-dihydrobenzofuran compound. Further, it provides novel benzoxazoleand 2,3-dihydrobenzofuran compounds which can be particularly usefullyused in the above-described pharmaceutical composition.

We claim:
 1. A 2,3-dihydrobenzofurane compound represented by thefollowing formula (Ia-2) or its pharmaceutically acceptable salt:##STR223## wherein P_(a), Q_(a) and R_(a) each independently stands fora hydrogen atom, a halogen atom, an amino, nitro, cyano, carboxyl orhydroxyl group, a C₁ -C₂₀ alkyl, C₁ -C₂₀ alkoxy, C₁ -C₂₀ alkanoylamino,C₁ -C₂₀ monoalkylamino, C₁ -C₂₀ alkyloxycarbonyl, C₁ -C₂₀ alkanoyl or C₁-C₂₀ alkanoyloxy group, or a C₂ -C₂₆ dialkylamino group, provided that,two or more of P_(a), Q_(a) and R_(a) are not halogen atoms at the sametime; andthe alkyl portion of said groups may be interrupted by:##STR224## phenylene or phenyleneoxy, wherein R₁₃ stands for a hydrogenatom, a lower alkyl, or lower alkanoyl group, or 1 to 3 hydrogen atomson the carbon atoms of the alkyl portion may be substituted with aphenyl group or phenyloxy group, a halogen atom or a cyano group, andthe phenyl portion as the substituent may be substituted with a halogenatom, an amino, nitro, cyano, carboxyl or hydroxyl group, a C₁ -C₂₀alkyl, C₁ -C₂₀ alkoxy, C₁ -C₂₀ monoalkylamino, C₁ -C₂₀ alkanoylamino, C₁-C₂₀ alkyloxycarbonyl, C₁ -C₂₀ alkanoyl or C₁ -C₂₀ alkanoyloxy group, ora C₂ -C₂₆ dialkylamino group; and R₁ stands for a group selected fromthe group consisting of: (i) an unsubstituted C₅ -C₇ cycloalkyl or C₆cycloalkenyl group or a C₅ -C₇ cycloalkyl or C₆ cycloalkenyl groupsubstituted at a position other than the 1-position with a substituentbeing a C₁ -C₁₄ alkyl, C₁ -C₁₄ alkoxy, C₁ -C₁₄ alkanoylamino, C₁ -C₁₄monoalkylamino, C₁ -C₁₄ alkyloxycarbonyl, C₁ -C₁₄ alkanoyl or C₁ -C₁₄alkanoyloxy group or a C₂ -C₂₆ dialkylamino group; (ii) a grouprepresented by the formula: ##STR225## wherein R₉ and R₁₀ eachindependently stands for a hydrogen atom or a lower alkyl group, or maycombine with each other to form a C₃ -C₇ carbon ring; and R₁₁ stands fora substituted or unsubstituted C₁ -C₁₉ alkyl, C₂ -C₁₉ alkenyl, C₆ to C₁₀aryl, C₇ -C₁₉ arylalkyl, C₁ -C₁₉ alkanoyl or C₁ -C₁₉ alkanoyl grouphaving a C₄ -C₁₉ aromatic ring, provided that the substituent when saidgroups are substituted by a halogen atom, an amino, nitro, cyano,carboxyl or hydroxyl group, a C₁ -C₁₆ alkyl, C₁ -C₁₆ alkoxy, C₁ -C₁₆alkanoylamino, C₁ -C₁₆ monoalkylamino, C₁ -C₁₆ alkyloxycarbonyl, C₁ -C₁₆alkyanoyl or C₁ -C₁₆ alkanoyloxy group, or a C₂ -C₂₆ dialkylamino group;or R₁₁ stands for a group represented by the formula:

    --A--X--B

wherein A stands for a C₁ -C₁₂ alkylene chain; X stands for an oxygenatom, a sulfur atom, or a group represented by the formula: ##STR226##wherein R₁₂ stands for a hydrogen atom or a lower alkyl or loweralkanoyl group; and B stands for a substituted or unsubstituted C₁ -C₈alkyl, C₆ or C₁₀ aryl or C₇ -C₈ arylalkyl group, provided that thesubstituent when said groups are substituted is a halogen atom, anamino, nitro, cyano, carboxyl or hydroxyl group, a C₁ -C₁₂ alkyl, C₁-C₁₂ alkoxy, C₁ -C₁₂ monoalkylamino, C₁ -C₁₂ alkanoylamino, C₁ -C₁₂alkyloxycarbonyl, C₁ -C₁₂ alkanoyl acyl or C₁ -C₁ alkanoxyloxy group, ora C₂ -C₂₀ dialkylamino group; and (iii) a substituted or unsubstitutedphenyl group or a group represented by the formula: ##STR227## whereinany one of P_(b), Q_(b), R_(b) and S_(b) represents a bond with theremaining three substituents independently standing for a grouprepresented by the formula --R₃, provided that, when the phenyl group issubstituted, the substituent is present at the m- or p-position and thesubstituent is an amino, cyano, carboxyl or hydroxyl group, C₁ -C₁₆alkoxy, C₁ -C₁₆ monoalkylamino, C₁ -C₁₆ alkanoylamino, C₁ -C₁₆alkyloxycarbonyl, C₁ -C₁₆ alkanoyl or C₁ -C₁₆ alkanoyloxy groups, or aC₂ -C₂₆ dialkylamino group; and the alkyl portion of said groups may beinterrupted by: ##STR228## phenylene or phenyleneoxy, wherein R₁₃ standsfor a hydrogen atom, a lower alkyl, or lower alkanoyl group, or 1 to 3hydrogen atoms on the carbon atoms of the alkyl portion may besubstituted with a phenyl or phenyloxy group, a halogen atom or a cyanogroup, or the phenyl portion as the substituent may be substituted witha halogen atom, an amino, nitro, cyano, carboxyl or hydroxyl group or alower alkyl, lower alkoxy, lower monoalkylamino, lower dialkylamino,lower alkanoylamino, lower alkyloxycarbonyl, lower alkanoyl or loweralkanoyloxy group; R₂ stands for a hydrogen atom or a C₁ -C₈ alkylgroup; each R₃ independently stands for a hydrogen atom, a halogen atom,an amino, nitro, cyano, carboxyl or hydroxyl group, C₁ -C₂₀ alkyl, C₁-C₂₀ alkoxy, C₁ -C₂₀ monoalkylamino, C₁ -C₂₀ alkanoylamino, C₁ -C₂₀alkyloxycarbonyl, C₁ -C₂₀ alkanoyl or C₁ -C₂₀ alkanoyloxy group, or adialkylamino group, provided that, two or more of each R₃ are nothalogen atoms at the same time; and R₅, R₆, R₇ and R₈ each independentlystands for a hydrogen atom or a C₁ -C₂₀ alkyl group, or R₅ and R₆ or R₇and R₈ combine with a carbon atom bonded thereto to form a C₅ -C₇ carbonring; and n is 0 or 1, provided that when any one of P_(a), O_(a) andR_(a) stands for an alkanoylamino group and R₁ stands for: ##STR229##wherein R₁₁ represents the unsubstituted or substituted C₁ -C₁₉ alkylgroup, both of the alkyl group of the alkanoylamino group and the alkylgroup R₁₁ do not have carbon atoms of C₆ or less at the same time.
 2. Acompound and its pharmaceutically acceptable salt according to claim 1,wherein the n value is
 1. 3. A compound and its pharmaceuticallyacceptable salt according to claim 2, wherein the R₂ stands for ahydrogen atom.
 4. A compound and its pharmaceutically acceptable saltaccording to claim 1, wherein the n value is 0 (zero).
 5. A compound andits pharmaceutically acceptable salt according to claim 4, wherein theR_(a) stands for a group other than a hydrogen atom.
 6. A compound andits pharmaceutically acceptable salt according to claim 5, wherein theR₁ stands for a group represented by the formula: ##STR230## wherein theR₉, R₁₀ and R₁₁ are as defined above.
 7. A method for treatinghypercholesterolemia comprising administering, to a patient in need ofsuch treatment, a treatment effective amount of the pharmaceuticalcomposition comprising a 2,3-dihydrobenzofurane compound represented bythe following formula (I-2) or its pharmaceutically acceptable salt:##STR231## wherein any one of the P, Q, R and S is a group representedby the formula: ##STR232## with the remaining three substituents beingindependently a group represented by --R₃,wherein R₁ stands for a groupselected from the group consisting of: (i) an unsubstituted C₅ -C₇cycloalkyl or C₆ cycloalkenyl group or a C₅ -C₇ cycloalkyl or C₆cycloalkenyl group substituted at a position other than the 1-positionwith the substituent being a C₁ -C₁₄ alkyl, C₁ -C₁₄ alkoxy, C₁ -C₁₄alkanoylamino, C₁ -C₁₄ monoalkylamino, C₁ -C₁₄ alkyloxycarbonyl, C₁ -C₁₄alkanoyl or C₁ -C₁₄ alkanoyloxy group or a C₂ -C₂₆ dialkylamino group;(ii) a group represented by the formula: ##STR233## wherein R₉ and R₁₀each independently stands for a hydrogen atom or a lower alkyl group, ormay combine with each other to form a C₃ -C₇ carbon ring; and R₁₁ standsfor a substituted or unsubstituted C₁ -C₁₉ alkyl, C₂ -C₁₉ alkenyl, C₆ orC₁₀ aryl, C₇ -C₁₉ arylalkyl, C₁ -C₁₉ alkanoyl or C₁ -C₁₉ alkanoyl grouphaving a C₄ -C₁₉ aromatic ring, provided that the substituent, when saidgroups are substituted, is a halogen atom, an amino, nitro, cyano,carboxyl or hydroxyl group, a C₁ -C₁₆ monoalkylamino, C₁ -C₁₆alkyloxycarbonyl, C₁ -C₁₆ alkanoyl or C₁ -C₁₆ alkanoyloxy group, or a C₂-C₂₆ dialkylamino group; or R₁₁ stands for a group represented by theformula:

    --A--X--B

wherein A stands for a C₁ -C₁₂ alkylene chain; X stands for an oxygenatom, a sulfur atom, or a group represented by the formula: ##STR234##wherein R₁₂ stands for a hydrogen atom or a lower alkyl or loweralkanoyl group; and B stands for a substituted or unsubstituted C₁ -C₈alkyl, C₆ or C₁₀ aryl or C₇ -C₈ arylalkyl group, provided that thesubstituent, when said groups are substituted, is a halogen atom, anamino, nitro, cyano, carboxyl or hydroxyl group, a C₁ -C₁₂ alkyl, C₁-C₁₂ alkoxy, C₁ -C₁₂ monoalkylamino, C₁ -C₁₂ alkanoylamino, C₁ -C₁₂alkyloxycarbonyl, C₁ -C₁₂ alkanoyl acyl or C₁ -C₁₂ alkanoyloxy group, ora C₂ -C₂₀ dialkylamino group; and (iii) a substituted or unsubstitutedphenyl group or a group represented by the formula: ##STR235## whereinany one of P_(b), Q_(b), R_(b) and S_(b) represents a bond with theremaining three substituents independently standing for a grouprepresented by --R₃, provided that, when the phenyl group issubstituted, the substituent is present at the o-, m- or p-position andthe substituent is a halogen atom, an amino, nitro, cyano, carboxyl orhydroxyl group, a C₁ -C₁₆ alkyl, C₁ -C₁₆ alkoxy, C₁ -C₁₆ monoalkylamino,C₁ -C₁₆ alkanoylamino, C₁ -C₁₆ alkyloxycarbonyl, C₁ -C₁₆ alkanoyl or C₁-C₁₆ alkanoyloxy group, or a C₂ -C₂₆ dialkylamino group; and the alkylportion of said groups may be interrupted by: ##STR236## phenylene orphenyleneoxy, wherein R₁₃ stands for a hydrogen atom, a lower alkyl, orlower alkanoyl group, or 1 to 3 hydrogen atoms on the carbon atoms ofthe alkyl portion may be substituted with a phenyl or phenyloxy group, ahalogen atom or a cyano group, or the phenyl portion as the substituentmay be substituted with a halogen atom, an amino, nitro, cyano, carboxylor hydroxyl group or a lower alkyl, lower alkoxy, lower monoalkylamino,lower dialkyamino, lower alkanoylamino, lower alkyloxycarbonyl, loweralkanoyl or lower alkanoyloxy group; R₂ stands for a hydrogen atom or aC₁ -C₈ alkyl group; each R₃ independently stands for a hydrogen atom, ahalogen atom, an amino, nitro, cyano, carboxyl or hydroxyl group, C₁-C₂₀ alkyl, C₁ -C₂₀ alkoxy, C₁ -C₂₀ monoalkylamino, C₁ -C₂₀alkanoylamino, C₁ -C₂₀ alkyloxycarbonyl, C₁ -C₂₀ alkanoyl or C₁ -C₂₀alkanoyloxy group, or a C₂ -C₂₀ dialkylamino group; and R₅, R₆, R₇, andR₈ each independently stands for a hydrogen atom or a C₁ -C₂₀ alkylgroup, or R₅ and R₆ or R₇ and R₈ combine with a carbon atom bondedthereto to form a C₅ -C₇ carbon ring; and n is 0 or
 1. 8. A methodaccording to claim 7, wherein the substituent S stands for a grouprepresented by the formula: ##STR237## wherein R₁, R₂ and n are the sameas defined in claim 7.